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Nimer RM, Arjah S, Obeidat M, Jaradat SA, Zenati RA, Bustanji Y, Semreen MH, Dahabiyeh LA. Untargeted LC-MS/MS- based metabolomics profiling of colorectal cancer cell lines reveals potential hypoxia-associated biomarkers. J Pharm Biomed Anal 2025; 263:116912. [PMID: 40306139 DOI: 10.1016/j.jpba.2025.116912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/17/2025] [Accepted: 04/19/2025] [Indexed: 05/02/2025]
Abstract
Colorectal cancer (CRC), a common cancer of the large intestine, is influenced by metabolic reprogramming due to hypoxia. Novel biomarkers may be identified through metabolomics. While many CRC studies have reported metabolomic profiling, the metabolic profile of CRC in the context of oxygen content has yet to be elucidated. Comprehending the metabolic alterations in cancer cells transitioning from normoxia (NMX) to hypoxia (HPX) and anoxia (ANX) is essential for the formulation of drugs that target particular metabolic pathways. Our study aimed to find metabolic changes in the HCT-116 CRC cell line under ANX, HPX, and NMX conditions, as well as to investigate novel biomarkers for CRC utilizing liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics approaches. Our findings showed significant changes in 77 metabolites in HCT-116 CRC cells across ANX, HPX, and NMX conditions, with 34 metabolites significantly disrupted in HPX compared to NMX, and 64 metabolites significantly changed in HPX compared to ANX. Significant differences included glutathione, gamma-glutamylcysteine, glycerophosphocholine, adenosine monophosphate, 5'-methylthioadenosine, guanosine 5'-diphosphate, threonic acid, and L-acetylcarnitine. Comprehending the metabolic changes in HPX, ANX, and NMX may uncover new pathways that could be targeted for potential treatments.
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Affiliation(s)
- Refat M Nimer
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Sara Arjah
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Marya Obeidat
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Saied A Jaradat
- Princess Haya Biotechnology Center, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Ruba A Zenati
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Yasser Bustanji
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Mohammad H Semreen
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Lina A Dahabiyeh
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
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Zulkifli A, Nam HY, Ng WM, Yasin NF, Kamarul T. Roxadustat pre-conditioning and cyclic uniaxial stretching improve tenogenic differentiation potential of human adipose derived mesenchymal stromal cells. Tissue Cell 2025; 95:102828. [PMID: 40086111 DOI: 10.1016/j.tice.2025.102828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 02/23/2025] [Accepted: 02/25/2025] [Indexed: 03/16/2025]
Abstract
Tendon injuries represent a significant challenge to treat owing to their limited intrinsic reparative capacity. The use of mesenchymal stem cells (MSC) offers promising alternative therapeutic option to augments tendon repair. It is hypothesised that the activation of hypoxia inducible factor-1 alpha (HIF-1α), could facilitate the tendon repair process by promoting the proliferation and tenogenic differentiation of MSCs. To demonstrate this, a study was conducted incorporating the use of Roxadustat, a specific hypoxia mimetic mediator and cyclic uniaxial stretching at a frequency of 1 Hz and 8 % strain on adipose derived-mesenchymal stromal cells (ADMSCs). METHODS Cellular morphology, proliferation rate, tenogenic protein and gene expression levels from 8 different treatment groups were compared. These groups include untreated ADMSCs (Control), Roxadustat pre-conditioned ADMSCs (ROX), ADMSCs subjected CAY10585 treatment only (CAY), Roxadustat pre-conditioned ADMSCs with CAY10585 inhibition (ROX+CAY), ADMSCs subjected to uniaxial stretching only (S), Roxadustat pre-conditioned ADMSCs with uniaxial stretching (ROX+S), ADMSCs subjected CAY10585 with uniaxial stretching (CAY+S) and primary tenocytes (Tenocytes). RESULTS ROX+S group exhibited the highest expression of HIF-1α and demonstrated a significant up-regulation of collagen I and III expressions, increasing by 4.9 and 5.6-fold compared to ROX group, respectively. There is a significant increase of SCX, TNC, TNMD, COLI and COLIII expression in this combination treatment group; (SCX= 9.9, TNC= 12.6, TNMD= 7.0, COLI= 8.0 and COLIII= 10.0-fold). Conversely, the expression of the markers markedly reduced with HIF-1α inhibitor CAY10585. However, uniaxial stretching effectively counteracted the inhibitory effects of CAY10585 in the CAY+ S group, resulting in a 3.9-fold increase in SCX expression compared to CAY treatment alone. CONCLUSION HIF-1α accumulation promotes superior tenogenic differentiation of ADMSCs, suggesting that the combination of Roxadustat and cyclic uniaxial stretching may be a potential therapeutic mediator in tendon repair strategies.
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Affiliation(s)
- Amirah Zulkifli
- Tissue Engineering Group, National Orthopaedic Centre of Excellence for Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Hui Yin Nam
- Tissue Engineering Group, National Orthopaedic Centre of Excellence for Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; Department of Pre-clinical Sciences, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Selangor 43000, Malaysia.
| | - Wuey Min Ng
- Sunway Medical Centre, Bandar Sunway, Subang Jaya, Selangor 47500, Malaysia
| | - Nor Faissal Yasin
- Tissue Engineering Group, National Orthopaedic Centre of Excellence for Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Tunku Kamarul
- Tissue Engineering Group, National Orthopaedic Centre of Excellence for Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
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Bangolo A, Amoozgar B, Habibi M, Simms E, Nagesh VK, Wadhwani S, Wadhwani N, Auda A, Elias D, Mansour C, Abbott R, Jebara N, Zhang L, Gill S, Ahmed K, Ip A, Goy A, Cho C. Exploring the gut microbiome’s influence on cancer-associated anemia: Mechanisms, clinical challenges, and innovative therapies. World J Gastrointest Pharmacol Ther 2025; 16:105375. [DOI: 10.4292/wjgpt.v16.i2.105375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 06/03/2025] Open
Abstract
BACKGROUND Anemia is a prevalent and challenging complication in patients with hematologic and solid malignancies, which stems from the direct effects of malignancy, treatment-induced toxicities, and systemic inflammation. It affects patients’ survival, functional status, and quality of life profoundly. Recent literature has highlighted the emerging role of the gut microbiome in the pathogenesis of cancer-associated anemia. The gut microbiota, through its intricate interplay with iron metabolism, inflammatory pathways, and immune modulation, may either exacerbate or ameliorate anemia depending on its composition, and functional integrity. Dysbiosis, characterized by disruption in the gut microbial ecosystem, is very common in cancer patients. This microbial imbalance is implicated in anemia causation through diminished iron absorption, persistent low-grade inflammation, and suppression of erythropoiesis.
AIM To consolidate current evidence regarding the interplay between gut microbiome and anemia in the setting of malignancies. It aims to provide a detailed exploration of the mechanistic links between dysbiosis and anemia, identifies unique challenges associated with various cancer types, and evaluates the efficacy of microbiome-focused therapies. Through this integrative approach, the review seeks to establish a foundation for innovative clinical strategies aimed at mitigating anemia and improving patient outcomes in oncology.
METHODS A literature search was performed using multiple databases, including Google Scholar, PubMed, Scopus, and Web of Science, using a combination of keywords and Boolean operators to refine results. Keywords included “cancer-associated anemia”, “gut microbiome”, “intestinal microbiota”, “iron metabolism”, “gut dysbiosis”, “short-chain fatty acids”, “hematopoiesis”, “probiotics”, “prebiotics”, and “fecal microbiota transplantation”. Articles published in English between 2000 and December 2024 were included, with a focus on contemporary and relevant findings.
RESULTS Therapeutic strategies aimed at restoration of gut microbial homeostasis, such as probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation (FMT), can inhibit anemia-causing pathways by enhancing microbial diversity, suppressing detrimental flora, reducing systemic inflammation and optimizing nutrient absorption.
CONCLUSION Gut dysbiosis causes anemia and impairs response to chemotherapy in cancer patients. Microbiome-centered interventions, such as probiotics, prebiotics, dietary modifications, and FMT, have shown efficacy in restoring microbial balance, reducing inflammation, and enhancing nutrient bioavailability. Emerging approaches, including engineered probiotics and bacteriophage therapies, are promising precision-based, customizable solutions for various microbiome compositions and imbalances. Future research should focus on integrating microbiome-targeted strategies with established anemia therapies.
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Affiliation(s)
- Ayrton Bangolo
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Behzad Amoozgar
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Maryam Habibi
- Department of Research, Tulane National Primate Research Center, Covington, LA 70433, United States
| | - Elizabeth Simms
- Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, United States
| | - Vignesh K Nagesh
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shruti Wadhwani
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Nikita Wadhwani
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Auda Auda
- Department of Family Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Daniel Elias
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Charlene Mansour
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Robert Abbott
- Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nisrene Jebara
- Columbia University School of Nursing, New York, NY 10032, United States
| | - Lili Zhang
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Sarvarinder Gill
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Kareem Ahmed
- Department of Medicine, University of Washington, Seattle, WA 98195, United States
| | - Andrew Ip
- Division of Lymphoma, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Andre Goy
- Division of Lymphoma, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Christina Cho
- Division of Stem Cell Transplant and Cellular Therapy, John Theurer Cancer Center, Hackensack, NJ 07601, United States
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Lee J, McClure S, Weichselbaum RR, Mimee M. Designing live bacterial therapeutics for cancer. Adv Drug Deliv Rev 2025; 221:115579. [PMID: 40228606 PMCID: PMC12067981 DOI: 10.1016/j.addr.2025.115579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/26/2025] [Accepted: 04/09/2025] [Indexed: 04/16/2025]
Abstract
Humans are home to a diverse community of bacteria, many of which form symbiotic relationships with their host. Notably, tumors can also harbor their own unique bacterial populations that can influence tumor growth and progression. These bacteria, which selectively colonize hypoxic and acidic tumor microenvironments, present a novel therapeutic strategy to combat cancer. Advancements in synthetic biology enable us to safely and efficiently program therapeutic drug production in bacteria, further enhancing their potential. This review provides a comprehensive guide to utilizing bacteria for cancer treatment. We discuss key considerations for selecting bacterial strains, emphasizing their colonization efficiency, the delicate balance between safety and anti-tumor efficacy, and the availability of tools for genetic engineering. We also delve into strategies for precise spatiotemporal control of drug delivery to minimize adverse effects and maximize therapeutic impact, exploring recent examples of engineered bacteria designed to combat tumors. Finally, we address the underlying challenges and future prospects of bacterial cancer therapy. This review underscores the versatility of bacterial therapies and outlines strategies to fully harness their potential in the fight against cancer.
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Affiliation(s)
- Jaehyun Lee
- Department of Microbiology, University of Chicago, Chicago, IL 60637, USA
| | - Sandra McClure
- Department of Microbiology, University of Chicago, Chicago, IL 60637, USA; Duchoissois Family Institute, University of Chicago, Chicago, IL 60637, USA; Committee On Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago 60637, USA
| | - Mark Mimee
- Department of Microbiology, University of Chicago, Chicago, IL 60637, USA; Duchoissois Family Institute, University of Chicago, Chicago, IL 60637, USA; Committee On Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
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Lee JJ, Ng KY, Bakhtiar A. Extracellular matrix: unlocking new avenues in cancer treatment. Biomark Res 2025; 13:78. [PMID: 40426238 PMCID: PMC12117852 DOI: 10.1186/s40364-025-00757-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/05/2025] [Indexed: 05/29/2025] Open
Abstract
The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.
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Affiliation(s)
- Jia Jing Lee
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia
| | - Khuen Yen Ng
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia
| | - Athirah Bakhtiar
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Selangor, Malaysia.
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6
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Amate M, Tan JJ, Boudreault F, Grygorczyk R, Gervais T, Yu FTH. Single cell level analysis of ATP release kinetics and cell fate following ultrasound targeted microbubble cavitation using microscopy techniques. PLoS One 2025; 20:e0319318. [PMID: 40424275 PMCID: PMC12111609 DOI: 10.1371/journal.pone.0319318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/31/2025] [Indexed: 05/29/2025] Open
Abstract
It is known that ultrasound-targeted microbubble cavitation (UTMC) can induce vasodilation. This image-guided spatially targeted approach is called provascular therapy when used as a radiotherapy sensitizer in radiation oncology. Extracellular adenosine-5'-triphosphate (eATP), which plays an important role in vascular tone regulation, is released by cells following UTMC, possibly through sonoporation (formation of temporary and non-deadly pores in the cell membrane) and/or cell death. Herein, we were interested in quantifying UTMC-mediated ATP released in vitro using a microfluidics-based model and study its relationship with cell fate to better understand and improve bioeffects induced by UTMC. Lipid microbubbles (MB, Definity®), luciferin-luciferase (LL - for eATP quantification), and propidium iodide (PI - poration tracer) were flowed over HUVEC cells cultured in a microfluidic device. Ultrasound at 1 MHz, varying in pressure (peak negative pressure: 300, 400 kPa) and length (10, 100, 1000 cycles) were applied to the chip. The LL chemiluminescent signal after the ultrasound pulse was acquired with an EMCCD camera to characterize ATP release kinetics. Then, a viability assay was performed with calcein-AM. An in-house MATLAB program pairing eATP kinetics with PI/calcein data was used to classify cells into three categories (sonoporated, dead, and untreated). Within the testing conditions, a single UTMC pulse caused between 4% and 55% PI-positive (PI+) cells in the ultrasound-treated area. Amongst PI+ cells, we generally found more dead cells than sonoporated cells, except for milder pulses (300 kPa; 10 and 100 cycles). The analysis of individual responses of ATP release demonstrated that dead cells released more ATP (up to 22.4 ± 12.2 fmol/cell) than sonoporated cells (6.8 ± 3.4 fmol/cell) and at a faster release rate which peaked at 4s. This study showed that sonoporation plays a significant role in UTMC-mediated ATP release, advancing our understanding of UTMC's potential use as a radiosensitizer in solid tumors.
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Affiliation(s)
- Marie Amate
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Institut du cancer de Montréal, (ICM), Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Institute of Biomedical Engineering, Université de Montréal, Montreal, Quebec, Canada
| | - Ju Jing Tan
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Francis Boudreault
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
| | - Ryszard Grygorczyk
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Thomas Gervais
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Institut du cancer de Montréal, (ICM), Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Department of Engineering Physics, Polytechnique Montréal, Montreal, Quebec, Canada
| | - François T. H. Yu
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Institut du cancer de Montréal, (ICM), Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada
- Institute of Biomedical Engineering, Université de Montréal, Montreal, Quebec, Canada
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montreal, Quebec, Canada
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Tamura M, Takai M, Yamamoto M, Yashiro N, Taniguchi A, Kusumoto Y, Nagano S, Shimomura N, Tsujiuchi T. Lysophosphatidic acid (LPA) receptor signaling enhances malignant potential in highly migratory lung cancer cells under hypoxic conditions. Acta Histochem 2025; 127:152268. [PMID: 40412000 DOI: 10.1016/j.acthis.2025.152268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 05/11/2025] [Accepted: 05/15/2025] [Indexed: 05/27/2025]
Abstract
Hypoxia contributes to tumor progression, promoting cancer cell motility, invasion and metastasis. Lysophosphatidic acid (LPA) receptors are implicated in the pathogenesis of cancer. In this study, we investigated the role of LPA receptor signaling in modulating malignant behavior under hypoxic conditions (1 % O2) in lung cancer cells. We generated highly migratory A549-R12 cells from the parental lung cancer A549 cells for this purpose. LPAR1 and LPAR2 expression levels were lower in both A549 and A549-R12 cells cultured at 1 % O2 compared to those cultured at 21 % O2, while LPAR3 expression remained unchanged between the two cell lines. Cell motility increased in both A549 and A549-R12 cells cultured at 1 % O2. Notably, A549-R12 cells exhibited greater motility under 1 % O2 conditions than A549 cells. Treatment with AM966 (an LPA1 antagonist) and (2S)-OMPT (an LPA3 agonist) further increased the motility of A549-R12 cells, while GRI-977143 (an LPA2 agonist) decreased their motility. Moreover, the invasion activity of A549-R12 cells was higher than that of A549 cells, with 1 % O2 conditions significantly enhancing A549-R12 cell invasion. AM966 and (2S)-OMPT stimulated, whereas GRI-977143 inhibited, the invasion of A549-R12 cells. In the presence of LPA, cell viability to cisplatin (CDDP) was higher in A549-R12 cells cultured at both 21 % and 1 % O2 compared to A549 cells. These results suggest that LPA receptor signaling plays a key role in regulating malignant progression in highly migratory lung cancer cells under hypoxic conditions.
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Affiliation(s)
- Moemi Tamura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Miwa Takai
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Mao Yamamoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Narumi Yashiro
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Anri Taniguchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Yuka Kusumoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Shion Nagano
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Nanami Shimomura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan.
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Grossmannova K, Belvoncikova P, Puzderova B, Simko V, Csaderova L, Pastorek J, Barathova M. Carbonic anhydrase IX downregulation linked to disruption of HIF-1, NFκB and STAT3 pathways as a new mechanism of ibuprofen anti-cancer effect. PLoS One 2025; 20:e0323635. [PMID: 40408503 PMCID: PMC12101644 DOI: 10.1371/journal.pone.0323635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 04/10/2025] [Indexed: 05/25/2025] Open
Abstract
Numerous studies have highlighted the anti-cancer effects of nonsteroidal anti-inflammatory drugs (NSAIDs), although the underlying mechanisms remain unclear. This study focuses on elucidating the impact of the NSAID ibuprofen (IBU) on cancer cells exposed to hypoxia, as the hypoxic microenvironment significantly influences tumor progression, metastatic potential, and therapy resistance. Given that carbonic anhydrase IX (CA IX) is a key hypoxia-associated protein and a promising therapeutic target due to its tumor-specific expression, we primarily examined the impact of IBU on CA IX and the transcription factors regulating CA IX expression. We found that IBU downregulates expression and protein level of CA IX in hypoxic colon carcinoma and head and neck cancer cells, resulting in a reduction of membranous CA IX. To elucidate the mechanism of this phenomenon, we analyzed the key CA IX-regulating transcription factor HIF-1 and found decreased levels of the HIF-1α subunit in IBU-treated cells, leading to its impaired binding to the CA9 promotor. Analysis of another transcription factor involved in CA IX expression, NFκB, showed suppressed NFκB pathway under IBU treatment. Moreover, we demonstrated IBU-mediated induction in apoptosis in cancer cells, as well as a decrease in their ability to migrate. Our study is the first to demonstrate that ibuprofen downregulates carbonic anhydrase IX expression in hypoxic colon and head and neck tumor cells by decreasing HIF-1α levels. Additionally, ibuprofen impairs key transcription factors NFκB and STAT3, leading to reduced adaptation to hypoxic stress, decreased tumor cell viability, and migration. This indicates its potential as a therapeutic agent in combination therapy for colon carcinoma or head and neck cancer.
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Affiliation(s)
- Katarina Grossmannova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Petra Belvoncikova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Barbora Puzderova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Veronika Simko
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lucia Csaderova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | | | - Monika Barathova
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
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Maloba GO, Were T, Barasa E, Mohamed N, Arshi A, Gallyas F. Synergistic Effects of 2-Deoxyglucose and Diclofenac Sodium on Breast Cancer Cells: A Comparative Evaluation of MDA-231 and MCF7 Cells. Int J Mol Sci 2025; 26:4894. [PMID: 40430033 PMCID: PMC12112485 DOI: 10.3390/ijms26104894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Resistance of breast cancers to chemotherapy remains a global challenge to date. Drug combination studies between anti-cancer agents are increasingly becoming therapeutic strategies, geared towards alleviating breast cancers. Previously, 2-deoxyglucose has been shown to target and interrupt glycolysis. Available evidence also suggests that diclofenac, which was originally designed as a pain reliever, could inhibit the proliferation of breast cancer cells. However, the reverse Warburg effect and other metabolic reprogramming mechanisms in breast cancers limit the pharmacological application of both 2-deoxyglucose and diclofenac as mono-therapeutic agents. The present study explores the additive anti-cancer effects of 2-deoxyglucose and diclofenac sodium on breast cancer cells. In this study, MDA-231 and MCF7 cells were treated with 2-deoxyglucose and diclofenac sodium in single and combination doses before being evaluated for viability, cell growth, reactive oxygen species, apoptotic and necrotic phases, and migration abilities. Additionally, immunoblotting of pro-apoptotic proteins, Caspase-3 and Caspase-9, and a hypoxia-inducible factor-1 alpha, was also performed. The results showed that combination treatments of the cells with the drugs exhibited additive anti-cancer effects by limiting proliferation, enhancing cytotoxic reactive oxygen species generation, enhancing apoptosis and necrosis, limiting colony formation and expansion of cells, and inhibiting cell migration. The degrees of cytotoxicity of combined treatments were almost similar in both cell lines, although with minimal differences. Put together, these results reveal the novel synergistic effects of 2-deoxyglucose and diclofenac sodium on breast cancer cells, hence potentially elevating their pharmacological profile in the overall breast cancer therapy.
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Affiliation(s)
- Geofrey Ouma Maloba
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary; (G.O.M.); (N.M.); (A.A.)
| | - Tom Were
- Department of Pathology, Masinde Muliro University of Science and Technology, Kakamega 190-50100, Kenya; (T.W.); (E.B.)
| | - Erick Barasa
- Department of Pathology, Masinde Muliro University of Science and Technology, Kakamega 190-50100, Kenya; (T.W.); (E.B.)
| | - Nasreldeen Mohamed
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary; (G.O.M.); (N.M.); (A.A.)
| | - Arshi Arshi
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary; (G.O.M.); (N.M.); (A.A.)
| | - Ferenc Gallyas
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary; (G.O.M.); (N.M.); (A.A.)
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10
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Lip H, Zetrini A, Park E, Cai P, Abbasi AZ, Huyan T, Alradwan I, Rauth AM, Wu XY. Mitigating radioresistance mechanisms by polymer-lipid manganese dioxide nanoparticles enhances immunogenic cell death and antitumor immune response to facilitate abscopal effect in breast tumor models. Drug Deliv Transl Res 2025:10.1007/s13346-025-01873-1. [PMID: 40389728 DOI: 10.1007/s13346-025-01873-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2025] [Indexed: 05/21/2025]
Abstract
Breast cancer is the most diagnosed cancer and the second leading cause of cancer death in women. Although treatments with major anti-cancer modalities are largely successful, resistance to treatments including widely applied radiation therapy (RT) can occur due largely to the multifaceted mechanisms in the tumor microenvironment (TME). The present work investigated the ability of Polymer-Lipid-Manganese Dioxide Nanoparticles (PLMD) to overcome hypoxia-associated radioresistant mechanisms and enhance RT-induced immunogenic cell death (ICD) and anti-tumor immunity for inhibiting growth of primary and distant tumors (the abscopal effect). The results showed that PLMD plus RT significantly inhibited the clonogenic survival of murine EMT6 and 4T1 breast cancer cells under hypoxic condition compared to RT alone. Analysis of ICD biomarkers revealed that PLMD profoundly enhanced RT-induced ICD compared to RT alone in EMT6 and 4T1 cells under hypoxic conditions but not under normoxic conditions. In a syngeneic murine breast tumor model with 4T1 orthotopic tumor, the PLMD treatment reduced tumor hypoxia significantly; PLMD + RT combination therapy increased infiltration of cytotoxic CD8+ T cells and CD86+ macrophages and decreased infiltration of immunosuppressive Tregs and CD163+ macrophages, as compared to RT alone. Importantly, the PLMD + RT treatment generated an abscopal effect in a tumor growth experiment using a double-tumor model, where the growth of an untreated tumor was inhibited by treatment of a tumor grown on the opposite side. Overall, the PLMD + RT induced an anti-tumor immune response that inhibited both primary and distant tumor growths and extended median survival in the tumor model.
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Affiliation(s)
- HoYin Lip
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
| | - Abdulmottaleb Zetrini
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
- Department of Pharmaceutics, University of Tripoli, Tripoli, Libya
| | - Elliya Park
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
| | - Ping Cai
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
| | - Azhar Z Abbasi
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
| | - Ting Huyan
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
| | - Ibrahim Alradwan
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada
- Advanced Diagnostics & Therapeutics Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11461, Saudi Arabia
| | - Andrew M Rauth
- Department of Medical Biophysics and Radiation Oncology, University of Toronto, 610 University Ave, Toronto, ON, M5G 2M9, Canada
| | - Xiao Yu Wu
- Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada.
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11
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Qusairy Z, Rada M. Glycosylation in cancer: mechanisms, diagnostic markers, and therapeutic applications. Mol Cell Biochem 2025:10.1007/s11010-025-05303-1. [PMID: 40389792 DOI: 10.1007/s11010-025-05303-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 05/04/2025] [Indexed: 05/21/2025]
Abstract
Glycosylation, a key post-translational modification, plays a pivotal role in cancer progression by influencing critical processes such as protein folding, immune modulation, and intercellular signaling. Altered glycosylation patterns are increasingly recognized as fundamental drivers of tumorigenesis, contributing to key cancer hallmarks like enhanced tumor migration, metastasis, and immune evasion. These aberrant glycosylation signatures not only offer insights into cancer biology but also serve as valuable diagnostic markers and potential therapeutic targets across a range of malignancies. This review explores the mechanisms underlying glycosylation alterations in cancer. We discuss the molecular basis of these changes, including genetic mutations, epigenetic regulation, and oncogene-driven shifts in glycosylation pathways. Additionally, we highlight recent advancements in glycomics research, with a focus on how these alterations influence tumor progression, angiogenesis, and the tumor microenvironment. Furthermore, the review considers the clinical implications of glycosylation changes, including their role in resistance to anti-cancer therapies and their potential as biomarkers for personalized treatment strategies. By bridging fundamental glycosylation research with clinical applications, this review underscores the promise of glycosylation as both a diagnostic tool and a therapeutic target in oncology, offering new avenues for improved patient stratification and precision medicine.
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Affiliation(s)
- Zahraa Qusairy
- McGill University Health Center Research Institute, Montreal, QC, H4A 3J1, Canada
| | - Miran Rada
- Medical Laboratory Science, Komar University of Science and Technology, Qularaisi, Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq.
- Komar Cancer Research Program, Komar University of Science and Technology, Qularaisi, Sulaimani, Sulaymaniyah, Kurdistan Region, Iraq.
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12
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Larrea Murillo L, Green M, Mahon N, Saiani A, Tsigkou O. Modelling Cancer Pathophysiology: Mechanisms and Changes in the Extracellular Matrix During Cancer Initiation and Early Tumour Growth. Cancers (Basel) 2025; 17:1675. [PMID: 40427172 PMCID: PMC12110603 DOI: 10.3390/cancers17101675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes.
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Affiliation(s)
- Luis Larrea Murillo
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
| | - Megan Green
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Niall Mahon
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Alberto Saiani
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Olga Tsigkou
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
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13
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Shen H, Mudassar F, Ma S, Wang X, Nguyen S, Bal N, Huynh QS, Wang D, Chang C, Ing P, Varikatt W, Lai J, Gloss B, Holst J, O’Neill GM, Gee H, Cook KM, Hau E. Inhibition of mitochondrial bioenergetics and hypoxia to radiosensitize diffuse intrinsic pontine glioma. Neuro Oncol 2025; 27:1061-1075. [PMID: 39575457 PMCID: PMC12083227 DOI: 10.1093/neuonc/noae255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2025] Open
Abstract
BACKGROUND Diffuse intrinsic pontine gliomas (DIPGs) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides only temporary symptomatic relief due to radioresistance. Although hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic. Diffuse intrinsic pontine gliomas often contain histone mutations, which alter tumor metabolism and are also associated with radioresistance. Our objective was to identify the metabolic profiles of DIPG cells, detect hypoxia signatures, and uncover metabolism-linked mechanisms of radioresistance to improve tumor radiosensitivity. METHODS Using DIPG models combined with clinical datasets, we examined mitochondrial metabolism and signatures of hypoxia. We explored DIPG reliance on mitochondrial metabolism using extracellular flux assays and targeted metabolomics. In vitro and in vivo models were used to explore the mechanisms of targeting mitochondrial bioenergetics and hypoxia for radiosensitization. Treatment-induced transcriptomics and metabolomics were also investigated. RESULTS Comprehensive analyses of DIPG cells show signatures of enhanced oxidative phosphorylation (OXPHOS). We also identified increased expression of specific OXPHOS-related genes and signatures of hypoxia gene expression in datasets obtained from DIPG patients. We found the presence of hypoxia in orthotopic mouse models bearing DIPG tumors. These findings enabled us to develop a proof-of-concept treatment strategy to enhance radiosensitivity of DIPGs in vitro and in animal models. CONCLUSIONS Diffuse intrinsic pontine glioma cells rely on mitochondrial metabolism for growth, and targeting mitochondria disrupts bioenergetics, alleviates hypoxia, and enhances radiosensitivity. These findings warrant further exploration of OXPHOS inhibition as a radiosensitizing strategy for DIPG treatment.
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Affiliation(s)
- Han Shen
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Faiqa Mudassar
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Shiyong Ma
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, The Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Xingyu Wang
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, The Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Sandy Nguyen
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Neha Bal
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Quy-Susan Huynh
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Dongwei Wang
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Cecilia Chang
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Prunella Ing
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Winny Varikatt
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Joey Lai
- Westmead Research Hub Core Facilities, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Brian Gloss
- Westmead Research Hub Core Facilities, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Jeff Holst
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Geraldine M O’Neill
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Harriet Gee
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Western Sydney Radiation Oncology Network, Western Sydney Local Health District, Sydney, NSW, Australia
- Genome Integrity Unit, Children’s Medical Research Institute, Westmead, NSW, Australia
| | - Kristina M Cook
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Eric Hau
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Western Sydney Radiation Oncology Network, Western Sydney Local Health District, Sydney, NSW, Australia
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14
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Parodi I, Palamà MEF, Di Lisa D, Pastorino L, Lagazzo A, Falleroni F, Aiello M, Fato MM, Scaglione S. Core-Shell Hydrogels with Tunable Stiffness for Breast Cancer Tissue Modelling in an Organ-on-Chip System. Gels 2025; 11:356. [PMID: 40422376 DOI: 10.3390/gels11050356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/28/2025] Open
Abstract
Breast cancer remains the most common malignancy in women, yet, many patients fail to achieve full remission despite significant advancements. This is largely due to tumour heterogeneity and the limitations of current experimental models in accurately replicating the complexity of in vivo tumour environment. In this study, we present a compartmentalised alginate hydrogel platform as an innovative in vitro tool for three-dimensional breast cancer cell culture. To mimic the heterogeneity of tumour tissues, we developed a core-shell structure (3.5% alginate core and 2% alginate shell) that mimic the stiffer, denser internal tumour matrix. The human triple-negative breast cancer cell line (MDA-MB-231) was embedded in core-shell alginate gels to assess viability, proliferation and hypoxic activity. Over one week, good cells proliferation and viability was observed, especially in the softer shell. Interestingly, cells within the stiffer core were more positive to hypoxic marker expression (HIF-1α) than those embedded in the shell, confirming the presence of a hypoxic niche, as observed in vivo. When cultured in the MIVO® milli fluidic organ-on-chip resembling the physiological fluid flow conditions, cancer cells viability became comparable between core and shell hydrogel area, emphasising the importance of the fluid flow in nutrients diffusion within three-dimensional matrixes. Cisplatin chemotherapy treatment further highlighted these differences: under static conditions, cancer cell death was prominent in the softer shell, whereas cells in the stiffer core remained resistant to cisplatin. Conversely, drug diffusion was more homogeneous in the core-shell structured treated in the organ-on-chip, leading to a uniform reduction in cell viability. These findings suggest that integrating a compartmentalised core-shell cell laden alginate model with the millifluidic organ on chip offers a more physiologically relevant experimental approach to deepening cancer cell behaviour and drug response.
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Affiliation(s)
- Ilaria Parodi
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
- National Research Council of Italy, Institute of Electronic, Computer and Telecommunications Engineering (CNR-IEIIT), 16149 Genoa, Italy
| | | | - Donatella Di Lisa
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16131 Genoa, Italy
| | - Laura Pastorino
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
| | - Alberto Lagazzo
- Department of Civil, Chemical and Environmental Engineering, University of Genoa, 16145 Genoa, Italy
| | | | - Maurizio Aiello
- National Research Council of Italy, Institute of Electronic, Computer and Telecommunications Engineering (CNR-IEIIT), 16149 Genoa, Italy
- React4life S.p.A., 16152 Genoa, Italy
| | - Marco Massimo Fato
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
| | - Silvia Scaglione
- National Research Council of Italy, Institute of Electronic, Computer and Telecommunications Engineering (CNR-IEIIT), 16149 Genoa, Italy
- React4life S.p.A., 16152 Genoa, Italy
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15
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Tran NA, Moonshi SS, Lam AK, Lu CT, Vu CQ, Arai S, Ta HT. Nanomaterials in cancer starvation therapy: pioneering advances, therapeutic potential, and clinical challenges. Cancer Metastasis Rev 2025; 44:51. [PMID: 40347350 PMCID: PMC12065774 DOI: 10.1007/s10555-025-10267-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/29/2025] [Indexed: 05/12/2025]
Abstract
Gaining significant attention in recent years, starvation therapy based on the blocking nutrients supply to cancer cells via blood occlusion and metabolic interventions is a promisingly novel approach in cancer treatment. However, there are many crucial obstacles to overcome to achieve effective treatment, for example, poor-targeting delivery, cellular hypoxia, adverse effects, and ineffective monotherapy. The starvation-based multitherapy based on multifunctional nanomaterials can narrow these gaps and pave a promising way for future clinical translation. This review focuses on the progression in nanomaterials-mediated muti-therapeutic modalities based on starvation therapy in recent years and therapeutic limitations that prevent their clinical applications. Moreover, unlike previous reviews that focused on a single aspect of the field, this comprehensive review presents a broader perspective on starvation therapy by summarising advancements across its various therapeutic strategies.
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Affiliation(s)
- Nam Anh Tran
- School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia
| | - Shehzahdi S Moonshi
- School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia
| | - Alfred K Lam
- School of Medicine and Dentistry, Griffith University, Southport, QLD, 4215, Australia
- Gold Coast University Hospital, Southport, QLD, 4215, Australia
| | - Cu Tai Lu
- School of Medicine and Dentistry, Griffith University, Southport, QLD, 4215, Australia
- Gold Coast University Hospital, Southport, QLD, 4215, Australia
| | - Cong Quang Vu
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan
| | - Satoshi Arai
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan
| | - Hang Thu Ta
- School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia.
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16
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Yamamoto M, Takai M, Yashiro N, Tamura M, Kusumoto Y, Nagano S, Taniguchi A, Shimomura N, Tsujiuchi T. Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions. Adv Biol Regul 2025; 96:101098. [PMID: 40345063 DOI: 10.1016/j.jbior.2025.101098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/18/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl2) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA1 to LPA6) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl2. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl2. CoCl2 treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl2 was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl2-treated DLD-1 cells was suppressed by AM966 (LPA1 antagonist) and enhanced by GRI-977143 (LPA2 agonist). Conversely, CoCl2 treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl2-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl2-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl2-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl2 treatment.
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Affiliation(s)
- Mao Yamamoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Miwa Takai
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Narumi Yashiro
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Moemi Tamura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Yuka Kusumoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Shion Nagano
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Anri Taniguchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Nanami Shimomura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan.
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17
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Cai S, Wei X, Li Q, Jiang Z, Li L. Smart materials in pharmacological drug development: Neutrophils and its constituents for drug delivery and consequent antitumor effects. Mol Immunol 2025; 183:18-32. [PMID: 40318595 DOI: 10.1016/j.molimm.2025.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/17/2025] [Accepted: 04/22/2025] [Indexed: 05/07/2025]
Abstract
Neutrophil-based drug delivery systems for targeted therapy of cancer have been studied widely in the recent past. Chemotactic cytokines including colony-stimulating factors (CSFs) recruit various immune cells including the neutrophils to the tumor microenvironment (TME) leading to enhanced metastasis. These cytokines can be targeted effectively by immunotherapeutic agents such as checkpoint inhibitors and mAbs that can lead to systemic toxicity. To minimize the systemic adverse effects, camouflaged nanoparticles can be used significantly as alternative therapeutic agents. The neutrophil-interacting NPs and neutrophil membrane coated NPs have been exploited recently for their antitumor properties in vitro and pose limited systemic adverse effects in vivo. Neutrophil-derived exosomes derived from immune cells can efficiently escape immune-surveillance and pass through the blood-brain barrier. They possess several intrinsic properties in drug delivery as they are nano-sized, extremely biocompatible, non-immunogenic, biodegradable, stable and can carry targeting agents with limited toxicity and display antitumor properties. Also, neutrophil-based nanotherapy is dependent on factors such as neutrophil kinetics and the physicochemical properties of NPs such as size, shape, and surface chemistry. Therefore, neutrophil-based drug delivery for cancer therapy via the use of polymer nanoparticles is widely studied as their clinical appliance in nanomedicine is still at its infancy.
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Affiliation(s)
- Shengjie Cai
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Xuehan Wei
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Qian Li
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210028, China; Department of Oncology, Jiangsu Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210028, China; Department of Oncology, Ganyu Hospital of Traditional Chinese Medicine, Lianyungang, Jiangsu 222000, China
| | - Ziyu Jiang
- Department of Oncology, Lianyungang Integrated Traditional Chinese and Western Medicine Clinical College, Nanjing University of Chinese Medicine, Nanjing 222002, China; Department of Oncology, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, China.
| | - Lingchang Li
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210028, China; Department of Oncology, Jiangsu Integrated Traditional Chinese and Western Medicine Hospital, Nanjing 210028, China.
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18
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Amereh M, Seyfoori A, Shojaei S, Lane S, Zhao T, Shokrollahi Barough M, Lum JJ, Walter P, Akbari M. Tumoroid Model Reveals Synergistic Impairment of Metabolism by Iron Chelators and Temozolomide in Chemo-Resistant Patient-derived Glioblastoma Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412505. [PMID: 40285641 PMCID: PMC12120723 DOI: 10.1002/advs.202412505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 03/18/2025] [Indexed: 04/29/2025]
Abstract
Chemoresistance poses a significant clinical challenge in managing glioblastoma (GBM), limiting the long-term success of traditional treatments. Here, a 3D tumoroid model is used to investigate the metabolic sensitivity of temozolomide (TMZ)-resistant GBM cells to iron chelation by deferoxamine (DFO) and deferiprone (DFP). This work shows that TMZ-resistant GBM cells acquire stem-like characteristics, higher intracellular iron levels, higher expression of aconitase, and elevated reliance on oxidative phosphorylation and proteins associated with iron metabolism. Using a microphysiological model of GBM-on-a-chip consisting of extracellular matrix (ECM)-incorporated tumoroids, this work demonstrates that the combination of iron chelators with TMZ induces a synergistic effect on an in vitro tumoroid model of newly diagnosed and recurrent chemo-resistant patient-derived GBM and reduced their size and invasion. Investigating downstream metabolic variations reveal reduced intracellular iron, increased reactive oxygen species (ROS), upregulated hypoxia-inducible factor-1α, reduced viability, increased autophagy, upregulated ribonucleotide reductase (RRM2), arrested proliferation, and induced cell death in normoxic TMZ-resistant cells. Hypoxic cells, while showing similar results, display reduced responses to iron deficiency, less blebbing, and an induced autophagic flux, suggesting an adaptive mechanism associated with hypoxia. These findings show that co-treatment with iron chelators and TMZ induces a synergistic effect, making this combination a promising GBM therapy.
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Affiliation(s)
- Meitham Amereh
- Laboratory for Innovations in Micro Engineering (LiME)Department of Mechanical EngineeringUniversity of VictoriaVictoriaBCV8P 5C2Canada
| | - Amir Seyfoori
- Laboratory for Innovations in Micro Engineering (LiME)Department of Mechanical EngineeringUniversity of VictoriaVictoriaBCV8P 5C2Canada
| | - Shahla Shojaei
- Department of Human Anatomy and Cell ScienceMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegMBR3T 2N2Canada
| | - Sarah Lane
- Department of BiologyUniversity of VictoriaBCCanada
| | - Tian Zhao
- Trev and Joyce Deeley Research CentreBC CancerVictoriaBCV8R 6V5Canada
| | - Mahdieh Shokrollahi Barough
- Laboratory for Innovations in Micro Engineering (LiME)Department of Mechanical EngineeringUniversity of VictoriaVictoriaBCV8P 5C2Canada
| | - Julian J. Lum
- Trev and Joyce Deeley Research CentreBC CancerVictoriaBCV8R 6V5Canada
- Department of Biochemistry and MicrobiologyUniversity of VictoriaVictoriaBCV8W 2Y2Canada
| | | | - Mohsen Akbari
- Laboratory for Innovations in Micro Engineering (LiME)Department of Mechanical EngineeringUniversity of VictoriaVictoriaBCV8P 5C2Canada
- Terasaki Institute for Biomedical InnovationsLos AngelesCA91367USA
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19
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Navarro-Serer B, Wissler MF, Glover BK, Lerner MG, Oza HH, Wang V, Knutsdottir H, Shojaeian F, Noller K, Baskaran SG, Hughes S, Weaver AM, Wilentz D, Olayemi O, Bader JS, Fertig EJ, Gilkes DM, Wood LD. P4HA1 Mediates Hypoxia-Induced Invasion in Human Pancreatic Cancer Organoids. CANCER RESEARCH COMMUNICATIONS 2025; 5:881-895. [PMID: 40332386 PMCID: PMC12123483 DOI: 10.1158/2767-9764.crc-24-0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 10/26/2024] [Accepted: 05/02/2025] [Indexed: 05/08/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal prognosis. PDAC develops in a hypoxic environment in which cells adapt and activate processes to allow survival under low-oxygen conditions, some of which may enhance the ability of cancer cells to invade locally or metastasize distantly. Using human PDAC organoids, we determined that hypoxia consistently enhanced invasion across 11 patient-derived models. Using RNA sequencing of hypoxic invasive organoids (compared with matched invasive normoxic organoids from the same patients), we identified prolyl 4-hydroxylase subunit alpha 1 (P4HA1) as a potential regulator of PDAC invasion in hypoxia. Leveraging publicly available datasets from human tissue, we determined that P4HA1 is more highly expressed in PDAC compared with normal pancreatic tissue and that high P4HA1 expression correlates with poor patient prognosis. To further interrogate the role of P4HA1 in invasion of hypoxic patient-derived organoids, we quantified invasion in organoids modified to knockdown or overexpress P4HA1, demonstrating that P4HA1 is necessary for hypoxia-enhanced invasion and sufficient to increase invasion in normoxia in PDAC organoids. Our results identify P4HA1 as a driver of PDAC organoid invasion in hypoxia. SIGNIFICANCE This study demonstrates that hypoxia increases invasion across a cohort of human pancreatic cancer organoids and identifies the collagen-modifying enzyme P4HA1 as a driver of hypoxia-enhanced invasion. These results characterize a molecular mechanism by which the microenvironment alters tumor cell behavior and underscore new strategies to inhibit invasion.
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Affiliation(s)
| | - Maria F. Wissler
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Brandi K. Glover
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Michael G. Lerner
- Department of Physics, Engineering and Astronomy, Earlham College, Richmond, Indiana
| | - Harsh H. Oza
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Vania Wang
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Hidur Knutsdottir
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Fatemeh Shojaeian
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Kathleen Noller
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | - Sarah Hughes
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Alana M. Weaver
- Department of Physics, Engineering and Astronomy, Earlham College, Richmond, Indiana
| | - Daniel Wilentz
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | - Joel S. Bader
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Elana J. Fertig
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, Maryland
| | - Daniele M. Gilkes
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Laura D. Wood
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
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20
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Lui I, Schaefer K, Kirkemo LL, Zhou J, Perera RM, Leung KK, Wells JA. Hypoxia Induces Extensive Protein and Proteolytic Remodeling of the Cell Surface in Pancreatic Adenocarcinoma (PDAC) Cell Lines. J Proteome Res 2025. [PMID: 40312771 DOI: 10.1021/acs.jproteome.4c01037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
The tumor microenvironment (TME) plays a crucial role in cancer progression. Hypoxia is a hallmark of the TME and induces a cascade of molecular events that affect cellular processes involved in metabolism, metastasis, and proteolysis. In pancreatic ductal adenocarcinoma (PDAC), tumor tissues are extremely hypoxic. Here, we leveraged mass spectrometry technologies to examine hypoxia-induced alterations in the abundance and proteolytic modifications to cell surface and secreted proteins. Across four PDAC cell lines, we discovered extensive proteolytic remodeling of cell surface proteins involved in cellular adhesion and motility. Looking outward at the surrounding secreted space, we identified hypoxia-regulated secreted and proteolytically shed proteins involved in regulating the humoral immune and inflammatory response, and an upregulation of proteins involved in metabolic processing and tissue development. Combining cell surface N-terminomics and secretomics to evaluate the cellular response to hypoxia enabled us to identify significantly altered candidate proteins which may serve as potential biomarkers and therapeutic targets in PDAC. Furthermore, this approach provides a blueprint for studying dysregulated extracellular proteolysis in other cancers and inflammatory diseases.
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Affiliation(s)
- Irene Lui
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - Kaitlin Schaefer
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - Lisa L Kirkemo
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - Jie Zhou
- Department of Radiation and Oncology, University of Chicago, Chicago, Illinois 60637, United States
- Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
| | - Rushika M Perera
- Department of Anatomy, University of California San Francisco, San Francisco, California 94143, United States
| | - Kevin K Leung
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
| | - James A Wells
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, United States
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21
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Wang Z, Thakur C, Bi Z, Qiu Y, Zhang W, Ji H, Venkatesan AK, Cherukuri S, Liu KJ, Haley JD, Mao X, Meliker J, Chen F. 1,4-Dioxane Induces Epithelial-Mesenchymal Transition and Carcinogenesis in an Nrf2-Dependent Manner. J Extracell Vesicles 2025; 14:e70072. [PMID: 40304624 PMCID: PMC12042698 DOI: 10.1002/jev2.70072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/22/2025] [Accepted: 03/20/2025] [Indexed: 05/02/2025] Open
Abstract
The carcinogenic potential of the environmental pollutant 1,4-dioxane (1,4-D) in humans is not yet fully understood or recognised. In this study, we provide evidence that 1,4-D acts as a carcinogen in human epithelial cells. Using the human bronchial epithelial cell line BEAS-2B, with or without CRISPR-Cas9-mediated Nrf2 knockout, we demonstrate that continuous exposure to environmentally relevant concentrations of 1.25-20 ppm 1,4-D over 2 months induces malignant transformation in an Nrf2-dependent manner. Transformed cells exhibit enhanced anchorage-independent growth in soft agar, increased migration and invasion, and tumorigenic potential in a xenograft mouse model. Integrated RNA sequencing and proteomics analyses reveal that 1,4-D robustly activates Nrf2 signalling, driving extracellular vesicle (EV) biogenesis and cargo loading with syndecan 4 (SDC4) and other proteins, including COL12A1, CAPG and NNMT, which are associated with epithelial-mesenchymal transition (EMT) and cancer metastasis. Nrf2 knockout reduces SDC4 expression and its incorporation into EVs, leading to decreased EV uptake by recipient cells. Unlike EVs from 1,4-D-transformed WT cells, which enhance the proliferation, migration and invasion of recipient cells, EVs from 1,4-D-transformed Nrf2 KO cells exhibit a diminished capacity to promote these EMT properties. Furthermore, we demonstrate that the Nrf2 target gene SDC4, induced by 1,4-D and enriched in EVs, plays a critical role in EV uptake by recipient cells, thereby facilitating EMT propagation. Collectively, our findings suggest that 1,4-D is a human carcinogen, with its carcinogenicity largely dependent on Nrf2 activation, which orchestrates the biogenesis of EVs with EMT-promoting functions.
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Affiliation(s)
- Ziwei Wang
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Chitra Thakur
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Zhuoyue Bi
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Yiran Qiu
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Wenxuan Zhang
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Haoyan Ji
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Arjun K. Venkatesan
- Civil Engineering, School of Marine and Atmospheric SciencesStony Brook UniversityStony BrookNew YorkUSA
- Department of Civil and Environmental EngineeringNew Jersey Institute of TechnologyNewarkNew JerseyUSA
| | - Sashank Cherukuri
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Ke Jian Liu
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - John D. Haley
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Xinwei Mao
- Department of Civil Engineering, College of Engineering and Applied SciencesStony Brook UniversityStony BrookNew YorkUSA
- New York State Center for Clean Water TechnologyStony Brook UniversityStony BrookNew YorkUSA
| | - Jaymie Meliker
- Department of Family, Population and Preventive Medicine, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
| | - Fei Chen
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of MedicineStony Brook UniversityStony BrookNew YorkUSA
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22
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Bai Y, Osmundson EC, Donahue MJ, De Vis JB. Magnetic resonance imaging to detect tumor hypoxia in brain malignant disease: A systematic review of validation studies. Clin Transl Radiat Oncol 2025; 52:100940. [PMID: 40093743 PMCID: PMC11908384 DOI: 10.1016/j.ctro.2025.100940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025] Open
Abstract
Tumor hypoxia indicates a worse prognosis in brain malignancies; however, current gold-standard methods for assessing tumor hypoxia are invasive and often inaccessible. Magnetic Resonance Imaging (MRI) is widely available, but its validity for identifying tumor hypoxia or hypoxia-related neoangiogenesis is not well characterized. A systematic literature search was performed across PubMed and Embase Databases. The search query identified MRI studies that validated hypoxia-surrogate imaging sequences against gold-standard hypoxia or neoangiogenesis detection methods in patients with brain malignancies. Literature screen identified 23 manuscripts published between 2007 and 2022. Among conventional MRI sequences, peritumoral edema and signal change after contrast administration were associated with gold-standard oxygen-assessment methods. T2*- and T2'-derived measures were associated with gold-standard methods, while reports on quantitative measures of oxygen extraction fraction were conflicting. Fiber density, tissue cellularity, blood volume, vascular transit time, and permeability measurements were associated with gold-standard methods, whereas blood flow measurements yielded conflicting results. MRI measures are promising surrogates for tumor hypoxia or hypoxia-related neoangiogenesis. Additional studies are needed to reconcile disparate findings. Future sensitivity analyses are needed to establish the MRI methods most accurate at identifying tumor hypoxia.
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Affiliation(s)
- Y Bai
- Vanderbilt School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - E C Osmundson
- Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M J Donahue
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
| | - J B De Vis
- Department of Radiation Oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
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23
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Sharma R, Yadav J, Bhat SA, Musayev A, Myrzagulova S, Sharma D, Padha N, Saini M, Tuli HS, Singh T. Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research. Mol Neurobiol 2025; 62:6423-6466. [PMID: 39804528 DOI: 10.1007/s12035-024-04680-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 12/20/2024] [Indexed: 03/29/2025]
Abstract
This review explores the current understanding and recent advancements in neuroblastoma, one of the most common extracranial solid pediatric cancers, accounting for ~ 15% of childhood cancer-related mortality. The hallmarks of NBL, including angiogenesis, metastasis, apoptosis resistance, cell cycle dysregulation, drug resistance, and responses to hypoxia and ROS, underscore its complex biology. The tumor microenvironment's significance in disease progression is acknowledged in this study, along with the pivotal role of cancer stem cells in sustaining tumor growth and heterogeneity. A number of molecular signatures are being studied in order to better understand the disease, with many of them serving as targets for the development of new therapeutics. This includes inhibitor therapies for NBL patients, which notably concentrate on ALK signaling, MDM2, PI3K/Akt/mTOR, Wnt, and RAS-MAPK pathways, along with regulators of epigenetic mechanisms. Additionally, this study offers an extensive understanding of the molecular therapies used, such as monoclonal antibodies and CAR-T therapy, focused on both preclinical and clinical studies. Radiation therapy's evolving role and the promise of stem cell transplantation-mediated interventions underscore the dynamic landscape of NBL treatment. This study has also emphasized the recent progress in the field of diagnosis, encompassing the adoption of artificial intelligence and liquid biopsy as a non-intrusive approach for early detection and ongoing monitoring of NBL. Furthermore, the integration of innovative treatment approaches such as CRISPR-Cas9, and cancer stem cell therapy has also been emphasized in this review.
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Affiliation(s)
- Rishabh Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Jaya Yadav
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Sajad Ahmad Bhat
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
- Department of Biochemistry, NIMS University, Rajasthan, Jaipur, 303121, India
| | - Abdugani Musayev
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
| | | | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
| | - Nipun Padha
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Department of Zoology, Cluster University of Jammu, Jammu, 180001, India
| | - Manju Saini
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India.
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, (INMAS-DRDO), New Delhi, Delhi, 110054, India.
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24
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Yashiro N, Takai M, Yamamoto M, Kusumoto Y, Nagano S, Taniguchi A, Tamura M, Tsujiuchi T. Cellular responses to low nutrient conditions via activation of lysophosphatidic acid (LPA) receptor signaling in gastric cancer cells. Adv Biol Regul 2025; 96:101068. [PMID: 39626328 DOI: 10.1016/j.jbior.2024.101068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/22/2024] [Accepted: 11/27/2024] [Indexed: 05/31/2025]
Abstract
In the center of the solid tumor, abnormal vascular architecture impedes sufficient blood supply, leading to continuous hypoxia and nutrient deprivation for the tumor cells. Lysophosphatidic acid (LPA) receptor signaling is known to drive a range of malignant behaviors in cancer cells. This study aimed to explore the impact of LPA receptors on cellular functions in gastric cancer AGS cells cultured under low nutrient conditions. When AGS cells were cultured in media containing low glucose (2000 mg/L), low glutamine (1 mM), or low amino acids (50 % content), LPA receptor expression levels were significantly altered. The growth activity of AGS cells cultured in low glucose- and low amino acid-containing media was suppressed by LPA. Conversely, LPA increased the growth activity of AGS cells cultured in low glutamine-containing media. AGS cell motility increased under low glucose and low glutamine conditions, while low amino acid conditions decreased cell motility. Additionally, the viability of AGS cells in response to cisplatin (CDDP) was enhanced under low glucose, low glutamine, and low amino acid conditions. The motility and viability of AGS cells in response to CDDP were significantly increased by AM966 (LPA1 antagonist), GRI-977143 (LPA2 agonist) and (2S)-OMPT (LPA3 agonist). These results suggest that LPA receptor signaling is significantly implicated in regulating malignant properties in AGS cells under low nutrient conditions.
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Affiliation(s)
- Narumi Yashiro
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Miwa Takai
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Mao Yamamoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Yuka Kusumoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Shion Nagano
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Anri Taniguchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Moemi Tamura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan.
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25
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Mahmoudi Gharehbaba A, Soltanmohammadi F, Vandghanooni S, Eskandani M, Adibkia K. A comprehensive review on overcoming the multifaceted challenge of cancer multidrug resistance: The emerging role of mesoporous silica nanoparticles. Biomed Pharmacother 2025; 186:118045. [PMID: 40215648 DOI: 10.1016/j.biopha.2025.118045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/26/2025] [Accepted: 04/03/2025] [Indexed: 04/25/2025] Open
Abstract
Multidrug resistance (MDR) is a significant challenge in tumor treatment, severely reducing the effectiveness of anticancer drugs and contributing to high mortality rates. This article overviews the various factors involved in the development of MDR, such as changes in drug targets, increased DNA repair mechanisms, and the impact of the tumor microenvironment. It also emphasizes the potential of mesoporous silica nanoparticles (MSNs) as a drug delivery system to combat MDR. With their unique characteristics-such as a high surface area, adjustable pore sizes, and the ability to be functionalized for targeted delivery-MSNs serve as excellent carriers for the simultaneous delivery of chemotherapeutics and siRNAs aimed at reversing resistance pathways. The paper focuses on innovative methods using MSNs for direct intranuclear delivery of their cargos to overcome efflux barrier and improve the effectiveness of combination therapies. This review highlights a promising approach for enhancing cancer treatment outcomes by integrating advanced nanotechnology with traditional therapies, addressing the ongoing challenge of MDR in oncology.
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Affiliation(s)
- Adel Mahmoudi Gharehbaba
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Soltanmohammadi
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Eskandani
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Khosro Adibkia
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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Bi X, Deng Y, Chu C, Wei M, Zhao J, Zhao J, Wang Y, Yin T, Gou J, He H, Tang X, Li G, Zhang Y. Precision-targeted explosion of biomimetic nanoparticles for the effective treatment of uveal melanoma. Int J Pharm 2025; 675:125543. [PMID: 40164415 DOI: 10.1016/j.ijpharm.2025.125543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/13/2025] [Accepted: 03/28/2025] [Indexed: 04/02/2025]
Abstract
Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, originating from the melanocytes within the uvea. Currently, the treatment of ocular tumors predominantly relies on conventional approaches such as brachytherapy and enucleation. Despite the limited pharmaceutical treatment options for uveal melanoma (UM), the effectiveness of ocular drug delivery is hindered by the ocular barrier to local drug administration and the complex tumor microenvironment (TME). In response, biomimetic low-density lipoprotein nanoparticles (LD-DPVP NPs) with active targeting capabilities were designed. This nanodrug system combined photosensitizer (verteporfin, VP) with the tumor vascular normalization drug (dexamethasone, DEX) to achieve low-toxicity, high-efficacy treatment of intraocular tumors. After intravenous injection, the nanoparticles selectively targeted the tumor site and induced VP to produce reactive oxygen species (ROS) that killed tumor cells under near-infrared laser stimulation. The produced ROS could also trigger the cleavage of the DEX prodrug (DPD) and rapid release of DEX via breakage of the thioether bond (TK). Additionally, DEX could modulate the TME, improving the delivery of nanoparticles to the tumor and further enhancing the efficacy of LD-DPVP NPs. We believe the biomimetic nanoparticles designed in this study have a potential clinical application value in inhibiting UM growth and provided a promising strategy for addressing other ocular malignancies.
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Affiliation(s)
- Xiaoshuang Bi
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Yaxin Deng
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Chenxiao Chu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Mingli Wei
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Jiansong Zhao
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Jiaqi Zhao
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Yuying Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, 103 WenhuaRoad, shenyang 1100l6, Liaoning, China
| | - Tian Yin
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016 Liaoning, China
| | - JingXin Gou
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Haibing He
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Xing Tang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Guofei Li
- Shengjing Hospital of China Medical University, Department of Pharmacy, No. 36, Sanhao Street, Shenyang 110004, China.
| | - Yu Zhang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
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Zhang WX, Chen J, Guo Q, Lv QY, Song X, Cui HF. Reversal of doxorubicin-resistance of MCF-7/Adr cells via multiple regulations by glucose oxidase loaded AuNRs@MnO 2@SiO 2 nanocarriers. Colloids Surf B Biointerfaces 2025; 253:114748. [PMID: 40334474 DOI: 10.1016/j.colsurfb.2025.114748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/23/2025] [Accepted: 04/27/2025] [Indexed: 05/09/2025]
Abstract
Targeting to multiple MDR mechanisms is a desired strategy for efficient reversal of multidrug resistance (MDR). Herein, a multi-functional and hierarchical-structured AuNRs@MnO2@SiO2 (AMS) nanocarrier is reported for multiple regulations of MDR. The glucose oxidase (GOx) loaded AMS (AMS/G) showed efficient capabilities of hypoxia-relieving, O2-generation enhanced cancer starvation therapy (CST), and near-infrared (NIR) laser photothermal therapy (PTT) to MCF-7/Adr, a doxorubicin (Dox)-resistant breast cancer cell line. It was revealed that hypoxia inducible factor-1α and heat shock protein 90, can be significantly down-regulated by AMS/G. The Dox resistance and the adenosine triphosphate (ATP)-binding cassette (ABC) transporters: P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), can be dramatically reversed by the AMS/G+NIR treatment. Specifically, the hypoxia-relieving function can down-regulate all the three ABC transporters. The enhanced CST decreases the expression of MRP1. The PTT diminishes the BCRP and MRP1. Assisted by the multiple and synergistic reversal mechanisms, the Dox co-loaded AMS/G (AMS/D/G) with NIR laser significantly inhibited the cell proliferation, migration, and drug efflux at both normoxia and hypoxia conditions. Cell apoptosis is greatly induced in a caspase-3 dependent manner. Tumor ATP depletion and Dox accumulation were confirmed in vivo. The tumor growth inhibition is greatly and synergistically enhanced, without inducing obvious side effects. Collectively, the nanostructured AMS/D/G can inhibit multiple ABC transporters and provide a promisingly platform for highly efficient reversal of tumor drug resistance.
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Affiliation(s)
- Wen-Xing Zhang
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Junyang Chen
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Qian Guo
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Qi-Yan Lv
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Xiaojie Song
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China.
| | - Hui-Fang Cui
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China.
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D’Agostino M, Rol-Moreno J, Bec G, Kuhn L, Ennifar E, Simonetti A. A structural element within the 5'UTR of β-catenin mRNA modulates its translation under hypoxia. Nucleic Acids Res 2025; 53:gkaf321. [PMID: 40309781 PMCID: PMC12044334 DOI: 10.1093/nar/gkaf321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 04/03/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025] Open
Abstract
Tight regulation of translation initiation is crucial for cellular adaptation to environmental changes. Stress conditions like hypoxia trigger translational reprogramming of mRNAs encoding proteins essential for stress recovery and cell survival. Recent studies highlight alternative translation initiation pathways based on specific motifs in mRNA 5' untranslated regions (5'UTRs). Notably, β-catenin is of particular interest since maintaining its translation promotes cancer cell persistence and plasticity. β-Catenin, an oncogenic protein, plays a key role in Wnt signalling. Besides dysregulation of the β-catenin/Wnt pathway, chemotherapy-induced hypoxia leads to abnormal nuclear β-catenin accumulation, modulating gene expression linked to cancer progression and metastasis. However, the mechanism sustaining β-catenin translation in stressed cells remains elusive. To explore how β-catenin mRNA evades global translational blockade in hypoxic cancer cells, we analysed its 5'UTR and identified a translation regulatory element in cellulo. We discovered a GC-rich three-way junction (TWJ) structure within the β-catenin 5'UTR enhancing its hypoxia-driven translation. A polypurine region within the TWJ anchors eIF4B, eIF4A, and eIF4G2. Importantly, the TWJ makes β-catenin mRNA translation eIF4A-dependent and sensitive to silvestrol, a selective eIF4A inhibitor and promising anticancer agent. This study elucidates the 5'UTR-driven β-catenin mechanism under hypoxia, paving the way to inhibit its translation in cancer.
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Affiliation(s)
- Mattia D’Agostino
- Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 2 Allée Konrad Roetgen, Strasbourg 67084, France
| | - Javier Rol-Moreno
- Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 2 Allée Konrad Roetgen, Strasbourg 67084, France
- Sanofi-Aventis R&D, Strasbourg 67000, France
| | - Guillaume Bec
- Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 2 Allée Konrad Roetgen, Strasbourg 67084, France
| | - Lauriane Kuhn
- Institut de Biologie Moléculaire et Cellulaire du CNRS, Plateforme protéomique Strasbourg-Esplanade, Université de Strasbourg, 2 Allée Konrad Roentgen, Strasbourg 67084, France
| | - Eric Ennifar
- Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 2 Allée Konrad Roetgen, Strasbourg 67084, France
| | - Angelita Simonetti
- Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 2 Allée Konrad Roetgen, Strasbourg 67084, France
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Suleman M, Sayaf AM, Aftab S, Alissa M, Alghamdi A, Alghamdi SA, Alshehri MA, Yeoh KK, Crovella S, Shaito AA. Medicinal Phytocompounds as Potential Inhibitors of p300-HIF1α Interaction: A Structure-Based Screening and Molecular Dynamics Simulation Study. Pharmaceuticals (Basel) 2025; 18:602. [PMID: 40284037 PMCID: PMC12030413 DOI: 10.3390/ph18040602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/09/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible factor-1 (HIF-1). For HIF-1 to function under low oxygen conditions, it must interact with the transcriptional coactivator p300, a critical step for promoting cancer cell survival and adaptation in hypoxic environments. Methods: Consequently, we used drug design and molecular simulation techniques to screen phytochemical databases, including traditional Chinese and African medicine sources, for compounds that could disrupt the p300/HIF-1 interaction. Results: In this study, we identified potential compounds with high docking scores such as EA-176920 (-8.719), EA-46881231 (-8.642), SA-31161 (-9.580), SA-5280863 (-8.179), NE-5280362 (-10.287), NE-72276 (-9.017), NA-11210533 (-10.366), NA-11336960 (-7.818), TCM-5281792 (-12.648), and TCM-6441280 (-9.470 kcal/mol) as lead compounds. Furthermore, the compound with the highest docking score from each database (EA-176920, SA-31161, NE-5280362, NA-11210533, and TCM-5281792) was subjected to further analysis. The stable binding affinity of these compounds with p300 was confirmed by Post-simulation binding free energy (-22.0020 kcal/mol, -25.4499 kcal/mol, -32.4530 kcal/mol, -33.9918 kcal/mol, and -57.7755 kcal/mol, respectively) and KD analysis. Moreover, the selected compounds followed the Lipinski rules with favorable ADMET properties like efficient intestinal absorption, high water solubility, and no toxicity. Conclusions: Our findings highlight the potential of natural compounds to target key protein-protein interactions in cancer and lay the groundwork for future in vitro and in vivo studies to explore their therapeutic potential. Specifically, disrupting the p300/HIF-1 interaction could interfere with hypoxia-driven pathways that promote tumor growth, angiogenesis, and metastasis, offering a promising strategy to suppress cancer progression at the molecular level.
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Affiliation(s)
- Muhammad Suleman
- Laboratory of Animal Research Center (LARC), Qatar University, Doha P.O. Box 2713, Qatar;
- Center for Biotechnology and Microbiology, University of Swat, Swat 19200, Pakistan;
| | - Abrar Mohammad Sayaf
- School of Chemical Sciences, Universiti Sains Malaysia, Gelugor 10050, Penang, Malaysia; (A.M.S.); (K.K.Y.)
| | - Sohail Aftab
- Center for Biotechnology and Microbiology, University of Swat, Swat 19200, Pakistan;
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.A.); (A.A.); (S.A.A.); (M.A.A.)
| | - Abdullah Alghamdi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.A.); (A.A.); (S.A.A.); (M.A.A.)
| | - Suad A. Alghamdi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.A.); (A.A.); (S.A.A.); (M.A.A.)
| | - Mohammed A. Alshehri
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.A.); (A.A.); (S.A.A.); (M.A.A.)
| | - Kar Kheng Yeoh
- School of Chemical Sciences, Universiti Sains Malaysia, Gelugor 10050, Penang, Malaysia; (A.M.S.); (K.K.Y.)
| | - Sergio Crovella
- Laboratory of Animal Research Center (LARC), Qatar University, Doha P.O. Box 2713, Qatar;
| | - Abdullah A. Shaito
- Biomedical Research Center (BRC), Department of Biomedical Sciences at College of Health Sciences, and College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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Edvall C, Kale N, Tani S, Ambhore S, Hossain R, Ozoude C, Van Horsen K, Mohammad J, Tuvin DM, Kalathingal S, Loganathan J, Choi Y, Sathish V, Brown J, Mallik S. Hypoxia-Responsive Polymersomes for Stemness Reduction in Patient-Derived Solid Tumor Spheroids. ACS APPLIED BIO MATERIALS 2025; 8:2916-2926. [PMID: 40056142 DOI: 10.1021/acsabm.4c01735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2025]
Abstract
Aggressive solid tumors are associated with rapid growth, early hypoxia, a lack of targeted therapies, and a poor prognosis. The hypoxic niches within the rapidly growing solid tumors give rise to a stem-cell-like phenotype with higher metastasis and drug resistance. To overcome the drug resistance of these regions, we used hypoxia-responsive polymersomes with an encapsulated anticancer drug (doxorubicin, Dox) and a stemness modulator (all-trans retinoic acid, ATRA). Reductase enzymes overexpressed in hypoxia reduce the azobenzene linker of the polymers, disrupt the bilayer structure of the polymersomes, and release the encapsulated drugs. We used triple-negative breast cancer (TNBC) as a representative of aggressive and hypoxic solid tumors. We observed that ATRA synergistically enhanced the efficacy of Dox in killing cancer cells. A synergistic combination of the two drug-encapsulated polymersomes reduced the volumes of patient-derived TNBC spheroids by 90%. In contrast, Dox alone decreased the spheroid volumes by 70% and encapsulated ATRA by 19%. Mechanistic studies revealed that ATRA inhibited efflux pumps, leading to a higher concentration of doxorubicin within TNBC cells. In addition, the combination of encapsulated Dox and ATRA significantly decreased stemness expression of the TNBC cells in hypoxia compared to that of Dox alone.
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Affiliation(s)
- Connor Edvall
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Narendra Kale
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Sakurako Tani
- Department of Physics, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Shubhashri Ambhore
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Rayat Hossain
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Chukwuebuka Ozoude
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Karl Van Horsen
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Jiyan Mohammad
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Daniel M Tuvin
- Sanford Broadway Clinic,801 Broadway N, Fargo, North Dakota 58102, United States
| | - Santo Kalathingal
- Agathos Biologics,4837 Amber Valley Pkwy Suite 12, Fargo, North Dakota 58104, United States
| | - Jagadish Loganathan
- Agathos Biologics,4837 Amber Valley Pkwy Suite 12, Fargo, North Dakota 58104, United States
| | - Yongki Choi
- Department of Physics, North Dakota State University, Fargo, North Dakota 58105, United States
| | - Venkatachalem Sathish
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States
| | - James Brown
- Agathos Biologics,4837 Amber Valley Pkwy Suite 12, Fargo, North Dakota 58104, United States
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota 57007, United States
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31
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Cho SY, Eun HS, Kim J, Ko YD, Rou WS, Joo JS. The Solute Carrier Superfamily as Therapeutic Targets in Pancreatic Ductal Adenocarcinoma. Genes (Basel) 2025; 16:463. [PMID: 40282424 PMCID: PMC12027052 DOI: 10.3390/genes16040463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/10/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC), a challenging and malignant cancer, primarily originates from the exocrine cells of the pancreas. The superfamily of solute carrier (SLC) transporters, consisting of more than 450 proteins divided into 65 families, is integral to various cellular processes and represents a promising target in precision oncology. As therapeutic targets, SLC transporters are explored through an integrative analysis. MATERIALS AND METHODS The expression profiles of SLCs were systematically analyzed using mRNA data from The Cancer Genome Atlas (TCGA) and protein data from the Human Protein Atlas (HPA). Survival analysis was examined to evaluate the prognostic significance of SLC transporters for overall survival (OS) and disease-specific survival (DSS). Genetic alterations were examined using cBioPortal, while structural studies were performed with AlphaFold and AlphaMissense to predict functional impacts. Furthermore, Gene Set Enrichment Analysis (GSEA) was carried out to identify oncogenic pathways linked to SLC transporter expression. RESULTS SLC transporters were significantly upregulated in tumors relative to normal tissues. Higher expression levels of SLC39A10 (HR = 1.89, p = 0.0026), SLC22B5 (HR = 1.84, p = 0.0042), SLC55A2 (HR = 2.15, p = 0.00023), and SLC30A6 (HR = 1.90, p = 0.003) were strongly associated with unfavorable OS, highlighting their connection to poor prognosis in PDAC. GSEA highlighted that these four transporters are significantly involved in key oncogenic pathways, such as epithelial-mesenchymal transition (EMT), TNF-α signaling, and angiogenesis. CONCLUSIONS The study identifies four SLCs as therapeutic targets in PDAC, highlighting their crucial role in essential metabolic pathways. These findings lay the groundwork for developing next-generation metabolic anti-cancer treatment to improve survival for PDAC patients.
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Affiliation(s)
- Sang Yeon Cho
- Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea;
- CHOMEDICINE Inc., TIPS Town, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Hyuk Soo Eun
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Jaejeung Kim
- Department of Computer Science and Engineering, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Yun Dam Ko
- Seoul Teunteun Rehabilitation Clinic, Jeungpyeong-gun, Chungcheongbuk-do 27937, Republic of Korea
| | - Woo Sun Rou
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Jong Seok Joo
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
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Gao C, Gao A, Jiang Y, Gao R, Guo Y, Peng Z, Jiang W, Zhang M, Zhou Z, Yan C, Fang W, Hu H, Zhu G, Zhang J. Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis. Mol Cell 2025; 85:1525-1542.e10. [PMID: 40185097 DOI: 10.1016/j.molcel.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 01/12/2025] [Accepted: 03/07/2025] [Indexed: 04/07/2025]
Abstract
Hypoxia and dysregulated phase separation can both activate oncogenic transcriptomic profiles. However, whether hypoxia regulates transcription-associated phase separation remains unknown. Here, we find that zinc fingers and homeoboxes 2 (ZHX2) undergoes phase separation in response to hypoxia, promoting their occupancy on chromatin and activating a cluster of oncogene transcription that is enriched by metastatic genes distinct from the targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Hypoxia induces ZHX2 phase separation via a proline-rich intrinsically disordered region (IDR), enhancing phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTC-binding factor (CTCF) in condensates to alter chromatin looping, consequently driving metastatic gene transcription and cancer metastasis. Our findings provide significant insight into oncogene activation and suggest a phase-separation-based therapeutic strategy for cancer.
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Affiliation(s)
- Chuan Gao
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Ang Gao
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Yulong Jiang
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Ronghui Gao
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Yan Guo
- Lingang Laboratory, Shanghai 201210, China
| | - Zirou Peng
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Weiwei Jiang
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Mengyao Zhang
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Zirui Zhou
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Chaojun Yan
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Wentong Fang
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Hankun Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | | | - Jing Zhang
- Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Hubei Key Laboratory of Tumor Biological Behavior, Wuhan 430071, China.
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Ogura Y, Sun X, Zhang Z, Kawata K, Wu J, Matsubara R, Ozeki AN, Taniue K, Onoguchi-Mizutani R, Adachi S, Nakayama K, Goda N, Akimitsu N. Fragile X messenger ribonucleoprotein 1 (FMRP) regulates glycolytic gene expression under chronic hypoxia in HCT116 cells. Sci Rep 2025; 15:13273. [PMID: 40246883 PMCID: PMC12006372 DOI: 10.1038/s41598-025-91828-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 02/24/2025] [Indexed: 04/19/2025] Open
Abstract
Oxygen shortage, known as hypoxia, occurs commonly in both physiological and pathological conditions. Transcriptional regulation by hypoxia-inducible factors is a dominant regulatory mechanism controlling hypoxia-responsive genes during acute hypoxia; however, recent studies suggest that post-transcriptional regulation, including RNA degradation, also involves hypoxia-induced gene expression during the chronic hypoxia. In this study, we developed a method to quantify the contributions of RNA synthesis and degradation to differential gene expression, and identified 102 genes mainly regulated via RNA degradation under chronic hypoxia in HCT116 cells. Bioinformatics analysis showed that the genes mainly regulated by RNA degradation were involved in glycolysis. We examined changes in the RNA-binding ability of RNA-binding proteins by RNA interactome capture and statistical analysis using public databases. We identified fragile X messenger ribonucleoprotein 1 (FMRP) as an RNA-binding protein involved in the chronic hypoxia-induced increase in mRNAs encoding rate-limiting enzymes. This study emphasizes the importance of post-transcriptional gene regulation under chronic hypoxia in HCT116 cells.
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Affiliation(s)
- Yoko Ogura
- Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Xiaoning Sun
- Advanced Interdisciplinary Studies, Engineering Department, The University of Tokyo, Tokyo, Japan
| | - Zaijun Zhang
- Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Kentaro Kawata
- Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan.
| | - Jinyu Wu
- Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Ryuma Matsubara
- Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan
| | | | - Kenzui Taniue
- Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan
| | | | - Shungo Adachi
- Department of Proteomics, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Koh Nakayama
- Department of Pharmacology, School of Medicine, Asahikawa Medical University, Hokkaido, 078-8510, Japan
| | - Nobuhito Goda
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan
| | - Nobuyoshi Akimitsu
- Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan.
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Qin W, Chen B, Li X, Zhao W, Wang L, Zhang N, Wang X, Luo D, Liang Y, Li Y, Chen X, Chen T, Yang Q. Cancer-associated fibroblasts secrete CSF3 to promote TNBC progression via enhancing PGM2L1-dependent glycolysis reprogramming. Cell Death Dis 2025; 16:249. [PMID: 40185722 PMCID: PMC11971334 DOI: 10.1038/s41419-025-07580-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 02/28/2025] [Accepted: 03/20/2025] [Indexed: 04/07/2025]
Abstract
Triple-negative breast cancer (TNBC) is characterized by a pronounced hypoxic tumor microenvironment, with cancer-associated fibroblasts (CAFs) serving as the predominant cellular component and playing crucial roles in regulating tumor progression. However, the mechanism by which CAFs affect the biological behavior of tumor cells in hypoxic environment remain elusive. This study employed a bead-based multiplex immunoassay to analyze a panel of cytokines/chemokines and identified colony stimulating factor 3 (CSF3) as a significantly elevated component in the secretome of hypoxic CAFs. We found that CSF3 promoted the invasive behavior of TNBC cells by activating the downstream signaling pathway of its receptor, CSF3R. RNA sequencing analysis further revealed that phosphoglucomutase 2-like 1 (PGM2L1) is a downstream target of the CSF3/CSF3R signaling, enhancing the glycolysis pathway and providing energy to support the malignant phenotype of breast cancer. In vivo, we further confirmed that CSF3 promotes TNBC progression by targeting PGM2L1. These findings suggest that targeting CSF3/CSF3R may represent a potential therapeutic approach for TNBC.
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Affiliation(s)
- Wenqi Qin
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Bing Chen
- Biological Resource Center, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Xin Li
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Wenjing Zhao
- Biological Resource Center, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Lijuan Wang
- Biological Resource Center, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Ning Zhang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Xiaolong Wang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Dan Luo
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Yiran Liang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Yaming Li
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Xi Chen
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Tong Chen
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Qifeng Yang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
- Biological Resource Center, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
- Research Institute of Breast Cancer, Shandong University, Jinan, Shandong, PR China.
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Bhattacharya R, Avdieiev SS, Bukkuri A, Whelan CJ, Gatenby RA, Tsai KY, Brown JS. The Hallmarks of Cancer as Eco-Evolutionary Processes. Cancer Discov 2025; 15:685-701. [PMID: 40170539 DOI: 10.1158/2159-8290.cd-24-0861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/19/2024] [Accepted: 01/28/2025] [Indexed: 04/03/2025]
Abstract
SIGNIFICANCE Viewing the hallmarks as a sequence of adaptations captures the "why" behind the "how" of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.
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Affiliation(s)
- Ranjini Bhattacharya
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Cancer Biology, University of South Florida, Tampa, Florida
| | - Stanislav S Avdieiev
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Anuraag Bukkuri
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
- Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher J Whelan
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois
| | - Robert A Gatenby
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Kenneth Y Tsai
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Joel S Brown
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois
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Beerkens APM, Heskamp S, Reinema FV, Adema GJ, Span PN, Bussink J. Mitochondria Targeting of Oxidative Phosphorylation Inhibitors to Alleviate Hypoxia and Enhance Anticancer Treatment Efficacy. Clin Cancer Res 2025; 31:1186-1193. [PMID: 39898881 DOI: 10.1158/1078-0432.ccr-24-3296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/28/2024] [Accepted: 01/08/2025] [Indexed: 02/04/2025]
Abstract
Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity have hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared with healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243, and IACS-010759 and the potential of mitochondria-targeted OXPHOSi and their influence on reactive oxygen species production. Furthermore, the effect of the mitochondria-targeting moiety triphenylphosphonium on mitochondria is discussed as it affects mitochondrial bioenergetics.
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Affiliation(s)
- Anne P M Beerkens
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboudumc, Nijmegen, the Netherlands
| | - Sandra Heskamp
- Department of Medical Imaging, Radboudumc, Nijmegen, the Netherlands
| | - Flavia V Reinema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboudumc, Nijmegen, the Netherlands
| | - Gosse J Adema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboudumc, Nijmegen, the Netherlands
| | - Paul N Span
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboudumc, Nijmegen, the Netherlands
| | - Johan Bussink
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboudumc, Nijmegen, the Netherlands
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Sobti A, Skinner H, Wilke CT. Predictors of Radiation Resistance and Novel Radiation Sensitizers in Head and Neck Cancers: Advancing Radiotherapy Efficacy. Semin Radiat Oncol 2025; 35:224-242. [PMID: 40090749 DOI: 10.1016/j.semradonc.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/16/2025] [Accepted: 02/17/2025] [Indexed: 03/18/2025]
Abstract
Radiation resistance in head and neck squamous cell carcinoma (HNSCC), driven by intrinsic and extrinsic factors, poses a significant challenge in radiation oncology. The key contributors are tumor hypoxia, cancer stem cells, cell cycle checkpoint activation, and DNA repair processes (homologous recombination and non-homologous end-joining). Genetic modifications such as TP53 mutations, KRAS mutations, EGFR overexpression, and abnormalities in DNA repair proteins like BRCA1/2 additionally affect radiation sensitivity. Novel radiosensitizers targeting these pathways demonstrate the potential to overcome resistance. Hypoxia-activated drugs and gold nanoparticles enhance the efficacy of radiotherapy and facilitate targeted distribution. Integrating immunotherapy, especially immune checkpoint inhibitors, with radiation therapy, enhances anti-tumor responses and reduces resistance. Epigenetic alterations, such as DNA methylation and histone acetylation, significantly influence radiation response, with the potential for sensitization through histone deacetylase inhibitors and non-coding RNA regulators. Metabolic changes linked to glucose, lipid, and glutamine metabolism influence radiosensitivity, uncovering new targets for radiosensitization. Human papillomavirus (HPV)-associated malignancies exhibit increased radiosensitivity relative to other tumors due to impaired DNA repair mechanisms and heightened immunogenicity. Furthermore, understanding the interplay between HPV oncoproteins and p53 functionality can enhance treatment strategies for HPV-related cancers. Using DNA damage response inhibitors (PARP, ATM/ATR), cell cycle checkpoint inhibitors (WEE1, CHK1/2), and hypoxia-targeted agents as radiosensitizing strategies exhibit considerable promise. Immunomodulatory approaches, including PD-1 and CTLA-4 inhibitors in conjunction with radiation, enhance anti-tumor immunity. Future directions emphasize personalized radiation therapy using genetics, sophisticated medication delivery systems, adaptive radiotherapy, and real-time monitoring. These integrated strategies seek to diminish radiation resistance and improve therapeutic efficacy in HNSCC.
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Affiliation(s)
- Aastha Sobti
- Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
| | - Heath Skinner
- Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
| | - Christopher T Wilke
- Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA..
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Zulkifli A, Kong P, Hrk S, Yasin NF, Nam HY, Kamarul T. Hypoxia-induced HIF-1α accumulation promotes superior tenogenic differentiation potential of human adipose-derived mesenchymal stromal cells. Biotech Histochem 2025; 100:100-118. [PMID: 40135543 DOI: 10.1080/10520295.2025.2482934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025] Open
Abstract
Tendon injuries remains a challenge to treat owing to its poor intrinsic reparative ability. It is hypothesised that hypoxic conditioning of mesenchymal stem cells (MSC) through the activation of hypoxia-inducible factor-1 alpha (HIF-1α), may enhance tendon repair process by promoting cellular proliferation and tenogenic differentiation. To demonstrate this, a study using roxadustat, a specific hypoxia mimetic mediator and HIF-1α inducer was conducted on adipose-derived mesenchymal stromal cells (AD-MSCs). Cellular morphology, proliferation rates, tenogenic protein and gene expression levels in untreated AD-MSCs (Group 1), roxadustat pre-conditioned AD-MSCs (Group 2), AD-MSCs subjected to CAY10585 (Group 3), roxadustat pre-conditioned AD-MSCs with CAY10585 (Group 4) and untreated primary tenocytes (Group 5) were evaluated. MSCs pre-conditioned with 12.5µM roxadustat for 24 hours showed the highest expression of HIF-1α without affecting the proliferation rates of AD-MSCs. However, significant reduction of HIF-1α levels was observed when the cells were treated with 3.5µM CAY10585. Roxadustat significantly up-regulated collagen I and III expressions by 6.6 and 6.3-fold respectively. HIF-1α promoted Scleraxis, Tenascin-C and Collagen III expressions, resulting in an increase of 6, 7, and 3 folds respectively. Conversely, using CAY10585 reduced these expressions to 3, 2 and 1 folds respectively. These trends were observed in the gene expression levels across Groups 1 to 4. However, the expression of these genes in Group 2 was significantly lower as compared to Group 5. Conclusion: HIF-1α accumulation promotes superior cell proliferation and tenogenic differentiation of AD-MSCs, indicating that roxadustat may be a potential therapeutic mediator in tendon repair strategies.
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Affiliation(s)
- Amirah Zulkifli
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya Malaya, Kuala Lumpur, Malaysia
| | - Peggy Kong
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya Malaya, Kuala Lumpur, Malaysia
| | - Shaliny Hrk
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya Malaya, Kuala Lumpur, Malaysia
| | - Nor Faissal Yasin
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya Malaya, Kuala Lumpur, Malaysia
| | - Hui Yin Nam
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya Malaya, Kuala Lumpur, Malaysia
- Nanotechnology & Catalysis Research Centre (NANOCAT), Institute for Advanced Studies, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Tunku Kamarul
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya Malaya, Kuala Lumpur, Malaysia
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Sharma R, Kashyap M, Zayed H, Krishnia L, Kashyap MK. Artificial blood-hope and the challenges to combat tumor hypoxia for anti-cancer therapy. Med Biol Eng Comput 2025; 63:933-957. [PMID: 39614063 DOI: 10.1007/s11517-024-03233-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 10/22/2024] [Indexed: 12/01/2024]
Abstract
The blood plays a vital role in the human body and serves as an intermediary between various physiological systems and organs. White blood cells, which are a part of the immune system, defend against infections and regulate the body temperature and pH balance. Blood platelets play a crucial role in clotting, the prevention of excessive bleeding, and the promotion of healing. Blood also serves as a courier system that transports hormones to facilitate communication and synchronization between different organs and systems in the body. The circulatory system, comprised of arteries, veins, and capillaries, plays a crucial role in the efficient transportation and connection of vital nutrients and oxygen. Despite the importance of natural blood, there are often supply shortages, compatibility issues, and medical conditions, which make alternatives such as artificial blood necessary. This is particularly relevant in cancer treatment, which was the focus of our study. In this study, we investigated the potential of artificial blood in cancer therapy, specifically to address tumor hypoxia. We also examined the potential of red blood cell substitutes such as hemoglobin-based oxygen carriers and perfluorocarbons. Additionally, we examined the production of hemoglobin using E. coli and the role of hemoglobin in oncogenesis. Furthermore, we explored the potential use of artificial platelets for cancer treatment. Our study emphasizes the significance of artificial blood in improving cancer treatment outcomes.
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Affiliation(s)
- Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon, Manesar (Gurugram), Haryana, 122413, India
| | - Manju Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon, Manesar (Gurugram), Haryana, 122413, India
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Lucky Krishnia
- Amity Institute of Nanotechnology, Amity School of Applied Sciences, Amity University Haryana, Panchgaon, Manesar (Gurugram), Haryana, 122413, India.
| | - Manoj Kumar Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon, Manesar (Gurugram), Haryana, 122413, India.
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Yuan W, Lu G, Zhao Y, He X, Liao S, Wang Z, Lei X, Xie Z, Yang X, Tang S, Tang G, Deng X. Intranuclear TCA and mitochondrial overload: The nascent sprout of tumors metabolism. Cancer Lett 2025; 613:217527. [PMID: 39909232 DOI: 10.1016/j.canlet.2025.217527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/19/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
Abnormal glucose metabolism in tumors is a well-known form of metabolic reprogramming in tumor cells, the most representative of which, the Warburg effect, has been widely studied and discussed since its discovery. However, contradictions in a large number of studies and suboptimal efficacy of drugs targeting glycolysis have prompted us to further deepen our understanding of glucose metabolism in tumors. Here, we review recent studies on mitochondrial overload, nuclear localization of metabolizing enzymes, and intranuclear TCA (nTCA) in the context of the anomalies produced by inhibition of the Warburg effect. We provide plausible explanations for many of the contradictory points in the existing studies, including the causes of the Warburg effect. Furthermore, we provide a detailed prospective discussion of these studies in the context of these new findings, providing new ideas for the use of nTCA and mitochondrial overload in tumor therapy.
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Affiliation(s)
- Weixi Yuan
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Guozhong Lu
- 922nd Hospital of Hengyang, 421001, Hunan, China
| | - Yin Zhao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiang He
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Senyi Liao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhe Wang
- The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoyong Lei
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Zhizhong Xie
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoyan Yang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Shengsong Tang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systems (2018TP1044), Hunan, 410007, China.
| | - Guotao Tang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Xiangping Deng
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Eghbalifard N, Nouri N, Rouzbahani S, Bakhshi M, Ghasemi Kahrizsangi N, Golafshan F, Abbasi F. Hypoxia signaling in cancer: HIF-1α stimulated by COVID-19 can lead to cancer progression and chemo-resistance in oral squamous cell carcinoma (OSCC). Discov Oncol 2025; 16:399. [PMID: 40138101 PMCID: PMC11947373 DOI: 10.1007/s12672-025-02150-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
The potential implications of Coronavirus disease-2019 (COVID-19) on oral squamous cell carcinoma (OSCC) development, chemo-resistance, tumor recurrence, and patient outcomes are explored, emphasizing the urgent need for tailored therapeutic strategies to mitigate these risks. The role of hypoxia-inducible factor 1-alpha (HIF-1α) in OSCC studies has highlighted HIF-1α as a crucial prognostic marker in OSCC, with implications for disease prognosis and patient survival. Its overexpression has been linked to aggressive subtypes in early OSCC stages, indicating its significance as an early biomarker for disease progression. Moreover, dysplastic lesions with heightened HIF-1α expression exhibit a greater propensity for malignant transformation, underscoring its role in early oral carcinogenesis. Cancer patients, including those with OSCC, face an elevated risk of severe COVID-19 complications, which may further impact cancer progression and treatment outcomes. Understanding the interplay between COVID-19 infection, HIF-1α activation, and OSCC pathogenesis is crucial for enhancing clinical management strategies. So, insights from this review shed light on the significance of HIF-1α in OSCC tumorigenesis, metastasis formation, and patient prognosis. The review underscores the need for further research to elucidate the precise mechanisms through which HIF-1α modulates cancer progression and chemo-resistance in the context of COVID-19 infection. Such knowledge is essential for developing targeted therapeutic interventions to improve outcomes for OSCC patients.
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Affiliation(s)
- Negar Eghbalifard
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nikta Nouri
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shiva Rouzbahani
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Bakhshi
- Islamic Azad University of Najaf Abad, Affiliated Hospitals, Isfahan, Iran
| | - Negin Ghasemi Kahrizsangi
- Child Growth and Development Research Center, Research Institute for Primary Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Faraz Golafshan
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Abbasi
- Department of Obstetrics and Gynecology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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42
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Grigoraș A, Amalinei C. The Role of Perirenal Adipose Tissue in Carcinogenesis-From Molecular Mechanism to Therapeutic Perspectives. Cancers (Basel) 2025; 17:1077. [PMID: 40227577 PMCID: PMC11987925 DOI: 10.3390/cancers17071077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 04/15/2025] Open
Abstract
Perirenal adipose tissue (PRAT) exhibits particular morphological features, with its activity being mainly related to thermogenesis. However, an expanded PRAT area seems to play a significant role in cardiovascular diseases, diabetes mellitus, and chronic kidney disease pathogenesis. Numerous studies have demonstrated that PRAT may support cancer progression and invasion, mainly in obese patients. The mechanism underlying these processes is of dysregulation of PRAT's secretion of adipokines and pro-inflammatory cytokines, such as leptin, adiponectin, chemerin, apelin, omentin-1, vistatin, nesfatin-1, and other pro-inflammatory cytokines, modulated by tumor cells. Cancer cells may also induce a metabolic reprogramming of perirenal adipocytes, leading to increased lipids and lactate transfer to the tumor microenvironment, contributing to cancer growth in a hypoxic milieu. In addition, the PRAT browning process has been specifically detected in renal cell carcinoma (RCC), being characterized by upregulated expression of brown/beige adipocytes markers (UCP1, PPAR-ɣ, c/EBPα, and PGC1α) and downregulated white fat cells markers, such as LEPTIN, SHOX2, HOXC8, and HOXC9. Considering its multifaceted role in cancer, modulation of PRAT's role in tumor progression may open new directions for oncologic therapy improvement. Considering the increasing evidence of the relationship between PRAT and tumor cells, our review aims to provide a comprehensive analysis of the perirenal adipocytes' impact on tumor progression and metastasis.
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Affiliation(s)
- Adriana Grigoraș
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Histopathology, Institute of Legal Medicine, 700455 Iasi, Romania
| | - Cornelia Amalinei
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Histopathology, Institute of Legal Medicine, 700455 Iasi, Romania
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Wawrzak-Pienkowska K, Pienkowski T, Tankiewicz-Kwedlo A, Ciborowski M, Kurek K, Pawlak D. Differences in treatment outcome between translational platforms in developing therapies for gastrointestinal cancers. Eur J Pharmacol 2025; 991:177309. [PMID: 39870234 DOI: 10.1016/j.ejphar.2025.177309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 01/29/2025]
Abstract
The variability in translational models profoundly impacts the outcomes and predictive value of preclinical studies for gastrointestinal (GI) cancer treatments. Preclinical models, including 2D cell cultures, 3D organoids, patient-derived xenografts (PDXs), and animal models, provide distinct advantages and limitations in replicating the complex tumor microenvironment (TME) of human cancers. Each model's unique biological and structural differences contribute to discrepancies in treatment responses, challenging the direct translation of experimental results to clinical settings. While 2D cell cultures are cost-effective and suitable for high-throughput screening, they lack the 3D architecture and cellular interactions of the in vivo TME. Organoids offer a more comprehensive 3D structure that better mirrors tumor heterogeneity, yet they still face limitations in fully mimicking in vivo conditions, such as vascularization and immune cell interactions. PDXs, although more representative of human cancers due to their genetic fidelity and TME preservation, are costly and resource-intensive, with human stromal and immune components gradually replaced by murine counterparts over time. This review assesses the strengths and limitations of each model, highlighting recent advancements in translational platforms that incorporate complex TME features. Understanding the influence of model selection on treatment efficacy predictions is essential for enhancing the reliability of preclinical findings and advancing personalized therapeutic strategies for GI cancers.
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Affiliation(s)
- Katarzyna Wawrzak-Pienkowska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowskiej MC 24A Street, 15-276, Bialystok, Poland; Department of Gastroenterology, Hepatology and Internal Diseases, Voivodeship Hospital in Bialystok, Sklodowskiej MC 26, 15-278, Bialystok, Poland
| | - Tomasz Pienkowski
- Clinical Research Center, Medical University of Bialystok, Sklodowskiej MC 24A, 15-276, Bialystok, Poland
| | - Anna Tankiewicz-Kwedlo
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222, Białystok, Poland
| | - Michal Ciborowski
- Clinical Research Center, Medical University of Bialystok, Sklodowskiej MC 24A, 15-276, Bialystok, Poland
| | - Krzysztof Kurek
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowskiej MC 24A Street, 15-276, Bialystok, Poland
| | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222, Białystok, Poland.
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Zheng B, Iwanaszko M, Soliman SHA, Ishi Y, Gold S, Qiu R, Howard BC, Das M, Zhao Z, Hashizume R, Wang L, Shilatifard A. Ectopic expression of testis-specific transcription elongation factor in driving cancer. SCIENCE ADVANCES 2025; 11:eads4200. [PMID: 40085698 PMCID: PMC11908497 DOI: 10.1126/sciadv.ads4200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 02/06/2025] [Indexed: 03/16/2025]
Abstract
The testis-specific BET protein BRDT structurally resembles the ubiquitous BRD4 and is misexpressed in cancer, and we show that BRDT misexpression may affect lung cancer progression. BRDT knockdown in lung cancer cells slowed tumor growth and prolonged survival in a xenograft model. Comparative characterization of PTEFb complex participation and chromatin binding indicates BRD4-redundant and BRD4-distinct BRDT functions. Unlike dual depletion, individual BRD4 or BRDT knockdown did not impair transcriptional responses to hypoxia in BRDT-expressing cells, consistent with redundant function. However, BRD4 depletion/BRDT complementation revealed that BRDT can also release paused RNA polymerase II independently of its bromodomains as we previously demonstrated not to be required for Pol II pause/release function of BRD4, underscoring the functional importance of the C-terminal domains in both BRD4 and BRDT and their potential as therapeutic targets in solid tumors. Based on this study, future investigations should explore BRD4-distinct BRDT functions and BRDT misexpression driving cancer pathogenesis.
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Affiliation(s)
- Bin Zheng
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Marta Iwanaszko
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Shimaa Hassan AbdelAziz Soliman
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Yukitomo Ishi
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Sarah Gold
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ruxuan Qiu
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Benjamin Charles Howard
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Madhurima Das
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Zibo Zhao
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Rintaro Hashizume
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Lu Wang
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ali Shilatifard
- Simpson Querrey Institute for Epigenetics and the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Abad-Montero D, Gandioso A, Izquierdo-García E, Chumillas S, Rovira A, Bosch M, Jordà-Redondo M, Castaño D, Bonelli J, Novikov VV, Deyà A, Hernández JL, Galino J, Alberto ME, Francés-Monerris A, Nonell S, Gasser G, Marchán V. Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors. J Am Chem Soc 2025; 147:7360-7376. [PMID: 39953993 DOI: 10.1021/jacs.4c15036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Abstract
Hypoxia, a hallmark of many solid tumors, is linked to increased cancer aggressiveness, metastasis, and resistance to conventional therapies, leading to poor patient outcomes. This challenges the efficiency of photodynamic therapy (PDT), which relies on the generation of cytotoxic reactive oxygen species (ROS) through the irradiation of a photosensitizer (PS), a process partially dependent on oxygen levels. In this work, we introduce a novel family of potent PSs based on ruthenium(II) polypyridyl complexes with 2,2'-bipyridyl ligands derived from COUPY coumarins, termed COUBPYs. Ru-COUBPY complexes exhibit outstanding in vitro cytotoxicity against CT-26 cancer cells when irradiated with light within the phototherapeutic window, achieving nanomolar potency in both normoxic and hypoxic conditions while remaining nontoxic in the dark, leading to impressive phototoxic indices (>30,000). Their ability to generate both Type I and Type II ROS underpins their exceptional PDT efficiency. The lead compound of this study, SCV49, shows a favorable in vivo pharmacokinetic profile, excellent toxicological tolerability, and potent tumor growth inhibition in mice bearing subcutaneous CT-26 tumors at doses as low as 3 mg/kg upon irradiation with deep-red light (660 nm). These results allow us to propose SCV49 as a strong candidate for further preclinical development, particularly for treating large hypoxic solid tumors.
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Affiliation(s)
- Diego Abad-Montero
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
| | - Albert Gandioso
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France
| | - Eduardo Izquierdo-García
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France
| | - Sergi Chumillas
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
| | - Anna Rovira
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
| | - Manel Bosch
- Unitat de Microscòpia Òptica Avançada, Centres Científics i Tecnològics, Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain
| | - Mireia Jordà-Redondo
- Institut Químic de Sarrià, Universitat Ramon Llull, Vía Augusta 390, E-08017 Barcelona, Spain
| | - Davor Castaño
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
| | - Joaquín Bonelli
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
| | - Valentin V Novikov
- Departament de Química Inorgànica i Orgànica, Secció de Química Inorgànica, Universitat de Barcelona (UB), and Institute of Nanoscience and Nanotechnology of the University of Barcelona (IN2UB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
| | - Alba Deyà
- Health and Biomedicine Department, Leitat Technological Center, Carrer de la Innovació 2, E-08225 Terrassa, Spain
| | - José Luis Hernández
- Health and Biomedicine Department, Leitat Technological Center, Carrer de la Innovació 2, E-08225 Terrassa, Spain
| | - Jorge Galino
- Health and Biomedicine Department, Leitat Technological Center, Carrer de la Innovació 2, E-08225 Terrassa, Spain
| | - Marta E Alberto
- Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Arcavacata di Rende I-87036, Italy
| | | | - Santi Nonell
- Institut Químic de Sarrià, Universitat Ramon Llull, Vía Augusta 390, E-08017 Barcelona, Spain
| | - Gilles Gasser
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France
| | - Vicente Marchán
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain
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46
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Bader KB, Padilla F, Haworth KJ, Ellens N, Dalecki D, Miller DL, Wear KA. Overview of Therapeutic Ultrasound Applications and Safety Considerations: 2024 Update. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2025; 44:381-433. [PMID: 39526313 PMCID: PMC11796337 DOI: 10.1002/jum.16611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 10/11/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024]
Abstract
A 2012 review of therapeutic ultrasound was published to educate researchers and physicians on potential applications and concerns for unintended bioeffects (doi: 10.7863/jum.2012.31.4.623). This review serves as an update to the parent article, highlighting advances in therapeutic ultrasound over the past 12 years. In addition to general mechanisms for bioeffects produced by therapeutic ultrasound, current applications, and the pre-clinical and clinical stages are outlined. An overview is provided for image guidance methods to monitor and assess treatment progress. Finally, other topics relevant for the translation of therapeutic ultrasound are discussed, including computational modeling, tissue-mimicking phantoms, and quality assurance protocols.
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Affiliation(s)
| | - Frederic Padilla
- Gene Therapy ProgramFocused Ultrasound FoundationCharlottesvilleVirginiaUSA
- Department of RadiologyUniversity of Virginia Health SystemCharlottesvilleVirginiaUSA
| | - Kevin J. Haworth
- Department of PediatricsUniversity of CincinnatiCincinnatiOhioUnited States
- Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
- Department of Biomedical EngineeringUniversity of CincinnatiCincinnatiOhioUSA
| | | | - Diane Dalecki
- Department of Biomedical EngineeringUniversity of RochesterRochesterNew YorkUSA
| | - Douglas L. Miller
- Department of RadiologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Keith A. Wear
- Center for Devices and Radiological HealthU.S. Food and Drug AdministrationSilver SpringMarylandUSA
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47
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Robinson KS, Sennhenn P, Yuan DS, Liu H, Taddei D, Qian Y, Luo W. TMBIM6/BI-1 is an intracellular environmental regulator that induces paraptosis in cancer via ROS and Calcium-activated ERAD II pathways. Oncogene 2025; 44:494-512. [PMID: 39609612 PMCID: PMC11832424 DOI: 10.1038/s41388-024-03222-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/28/2024] [Accepted: 11/05/2024] [Indexed: 11/30/2024]
Abstract
Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, also known as Bax Inhibitor-1 (BI-1), has been heavily researched for its cytoprotective functions. TMBIM6 functional diversity includes modulating cell survival, stress, metabolism, cytoskeletal dynamics, organelle function, regulating cytosolic acidification, calcium, and reactive oxygen species (ROS). Clinical research shows TMBIM6 plays a key role in many of the world's top diseases/injuries (i.e., Alzheimer's, Parkinson's, diabetes, obesity, brain injury, liver disease, heart disease, aging, etc.), including cancer, where TMBIM6 expression impacts patient survival, chemoresistance, cancer progression, and metastasis. We show TMBIM6 is activated by, and undergoes, different conformational changes that dictate its function following a significant change in the cell's IntraCellular Environment (ICE). TMBIM6 agonism, following ICE change, can help the cell overcome multiple stresses including toxin exposure, viral infection, wound healing, and excitotoxicity. However, in cancer cells TMBIM6 agonism results in rapid paraptotic induction irrespective of the cancer type, sub-type, genotype or phenotype. Furthermore, the level of TMBIM6 expression in cancer did not dictate the level of paraptotic induction; however, it did dictate the rate at which paraptosis occurred. TMBIM6 agonism did not induce paraptosis in cancer via canonical routes involving p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9. Instead, TMBIM6 agonism in cancer upregulates cytosolic Ca2+ and ROS, activates lysosome biogenesis, and induces paraptosis via ERAD II mechanisms. In xenograft models, we show TMBIM6 agonism induces rapid cancer cell death with no toxicity, even at high doses of TMBIM6 agonist (>450 mg/kg). In summary, this study shows TMBIM6's functional diversity is only activated by severe ICE change in diseased/injured cells, highlighting its transformative potential as a therapeutic target across various diseases and injuries, including cancer.
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Affiliation(s)
| | | | | | - Hai Liu
- Viva Biotech, Shanghai, China
| | | | | | - Wei Luo
- MicroQuin, Cambridge, MA, USA
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48
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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49
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Marks C, Leech M. Optimising hypoxia PET imaging and its applications in guiding targeted radiation therapy for non-small cell lung cancer: a scoping review. J Med Radiat Sci 2025; 72:106-118. [PMID: 39422481 PMCID: PMC11909692 DOI: 10.1002/jmrs.831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 09/28/2024] [Indexed: 10/19/2024] Open
Abstract
INTRODUCTION Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Definitive treatment includes chemotherapy and radiation therapy. Tumour hypoxia impacts the efficacy of these treatment modalities. Novel positron-emission tomography (PET) imaging has been developed to non-invasively quantify hypoxic tumour subregions, and to guide personalised treatment strategies. This review evaluates the reliability of hypoxia imaging in NSCLC in relation to various tracers, its correlations to treatment-related outcomes, and to assess if this imaging modality can be meaningfully applied into radiation therapy workflows. METHODS A literature search was conducted on the Medline (Ovid) and Embase databases. Searches included terms related to 'hypoxia', 'positron-emission tomography', 'magnetic resonance imaging' and 'lung cancer'. Results were filtered to exclude studies prior to 2011, and animal studies were excluded. Only studies referring to a confirmed pathology of NSCLC were included, while disease staging was not a limiting factor. Full-text English language and translated literature examined included clinical trials, clinical cohort studies and feasibility studies. RESULTS Quantification of hypoxic volumes in a pre-treatment setting is of prognostic value, and indicative of treatment response. Dosimetric comparisons have highlighted potential to significantly dose escalate to hypoxic volumes without risk of additional toxicity. However, clinical data to support these strategies are lacking. CONCLUSION Heterogenous study design and non-standardised imaging parameters have led to a lack of clarity regarding the application of hypoxia PET imaging in NSCLC. PET imaging using nitroimidazole tracers is the most investigated method of non-invasively measuring tumour hypoxia and has potential to guide hypoxia-targeted radiation therapy. Further clinical research is required to elucidate the benefits versus risks of dose-escalation strategies.
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Affiliation(s)
- Carol Marks
- Applied Radiation Therapy Trinity, Trinity St. James's Cancer Institute, Discipline of Radiation TherapyTrinity College DublinDublinIreland
| | - Michelle Leech
- Applied Radiation Therapy Trinity, Trinity St. James's Cancer Institute, Discipline of Radiation TherapyTrinity College DublinDublinIreland
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50
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Masarkar N, Pal M, Roy M, Yadav AK, Pandya B, Lokhande S, Kanwar JR, Ray SK, Mukherjee S. In-silico screening of bioactive compounds of Moringa oleifera as potential inhibitors targeting HIF-1α/VEGF/GLUT-1 pathway against breast cancer. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2025; 22:149-164. [PMID: 39024644 DOI: 10.1515/jcim-2024-0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 06/24/2024] [Indexed: 07/20/2024]
Abstract
OBJECTIVES Breast cancer is among the most heterogeneous and aggressive diseases and a foremost cause of death in women globally. Hypoxic activation of HIF-1α in breast cancers triggers the transcription of a battery of genes encoding proteins that facilitate tumor growth and metastasis and is correlated with a poor prognosis. Based on the reported cytotoxic and anti-cancer properties of Moringa oleifera (Mo), this study explores the inhibitory effect of bioactive compounds from M. oleifera and breast cancer target proteins HIF-1α, VEGF, and GLUT-1 in silico. METHODS The X-ray crystallographic structures of HIF-1α, VEGF, and GLUT1 were sourced from the Protein Data Bank (PDB) and docked with 70 3D PubChem structures of bioactive compounds of M. oleifera using AutoDock Vina, and binding modes were analyzed using Discovery Studio. Five compounds with the highest binding energies were selected and further drug-likeness, oral bioavailability, ADME, and toxicity profiles were analyzed using SwissADME, ADMETSaR, and ADMETlab 3.0 web server. RESULTS Out of the screened 70 bioactive compounds, the top five compounds with the best binding energies were identified namely Apigenin, Ellagic Acid, Isorhamnetin, Luteolin, and Myricetin with each receptor. Molecular docking results indicated that the ligands interact strongly with the target HIF-1α, VEGF, and GLUT-1 receptors through hydrogen bonds and hydrophobic interactions. These compounds showed favorable drug-like and pharmacokinetic properties, possessed no substantial toxicity, and were fairly bioavailable. CONCLUSIONS Results suggested that the compounds possess strong potential in developing putative lead compounds targeting HIF-1α that are safe natural plant-based drugs against breast cancer.
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Affiliation(s)
- Neha Masarkar
- Department of Biochemistry, 390706 All India Institute of Medical Sciences (AIIMS) Bhopal , Bhopal, Madhya Pradesh, India
| | - Maynak Pal
- Department of Chemistry, National Institute of Technology Manipur, Imphal, India
| | - Mithun Roy
- Department of Chemistry, National Institute of Technology Manipur, Imphal, India
| | - Ashish K Yadav
- Department of Biochemistry, 390706 All India Institute of Medical Sciences (AIIMS) Bhopal , Bhopal, Madhya Pradesh, India
| | - Bharati Pandya
- Department of General Surgery, All India Institute of Medical Sciences (AIIMS) Bhopal, Bhopal, India
| | - Suryabhan Lokhande
- Department of Biochemistry, 390706 All India Institute of Medical Sciences (AIIMS) Bhopal , Bhopal, Madhya Pradesh, India
| | - Jagat R Kanwar
- Department of Biochemistry, 390706 All India Institute of Medical Sciences (AIIMS) Bhopal , Bhopal, Madhya Pradesh, India
| | | | - Sukhes Mukherjee
- Department of Biochemistry, 390706 All India Institute of Medical Sciences (AIIMS) Bhopal , Bhopal, Madhya Pradesh, India
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