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Haffez H, Sanad HH, Ebrahim H, Hassan ZA. Synergistic effects of abietic acid combined with doxorubicin on apoptosis induction in a human colorectal cancer cell line. Sci Rep 2025; 15:16102. [PMID: 40341222 PMCID: PMC12062260 DOI: 10.1038/s41598-025-99616-2] [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: 01/07/2025] [Accepted: 04/21/2025] [Indexed: 05/10/2025] Open
Abstract
Cancer is a significant global disease with high mortality and limited therapeutic options. Chemotherapy is a cancer treatment option; however, there are still issues, including severe side effects, inadequate response, and drug resistance. Abietic acid is a natural diterpene with diverse pharmacological properties and can be used for cancer treatment. Therefore, this study aimed to assess the anticancer efficacy of abietic acid in combination with doxorubicin, a highly clinically used chemotherapeutic agent. Biochemical investigations include initial viability assays, combination therapy using isobologram analysis, apoptosis and cell cycle assays, gene expression assay, ELISA analysis of protein expression, DNA fragmentation, and wound healing assays. The data showed that doxorubicin-abietic acid (DOX-AB) is an effective and safe anticancer combination for Caco-2 cells. DOX-AB had a high safety index with minimal cytotoxicity at the combination dose on normal WI-38 fibroblasts cells. DOX-AB significantly decreased the proliferation and viability of Caco-2 cells, with an increase in the apoptosis rate in the late stage and necrosis with cell cycle arrest at the G2/M phase. Significant changes in the expression of modulators related to apoptosis, inflammation, and epigenetics were observed in gene and protein levels. DOX-AB combination had more efficient anticancer activity than doxorubicin alone. This study suggested that the use of abietic acid in combination with doxorubicin is a promising treatment for colorectal cancer because it enhances doxorubicin activity at relatively low doses with minimal cytotoxicity and overcomes multidrug resistance in tumors; these findings merit further investigation.
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Affiliation(s)
- Hesham Haffez
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo, 11795, Egypt.
- Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, Cairo, 11795, Egypt.
| | - Hend H Sanad
- Health Affairs Directorate, Mansoura Health Administration, Mansura city, , El Dakahlia, Egypt
| | - Hassan Ebrahim
- Pharmacognosy Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt
| | - Zeineb A Hassan
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo, 11795, Egypt
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2
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Gu XY, Yang JL, Lai R, Zhou ZJ, Tang D, Hu L, Zhao LJ. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol 2025; 16:1563303. [PMID: 40207222 PMCID: PMC11979165 DOI: 10.3389/fimmu.2025.1563303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Li Yang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Lai
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zheng-Jun Zhou
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Dan Tang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Hepatobiliary and Pancreatic Surgery, Suzhou Medical College of Soochow University, Suzhou, China
| | - Long Hu
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
| | - Li-Jin Zhao
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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3
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Flores-García LC, García-Castillo V, Pérez-Toledo E, Trujano-Camacho S, Millán-Catalán O, Pérez-Yepez EA, Coronel-Hernández J, Rodríguez-Dorantes M, Jacobo-Herrera N, Pérez-Plasencia C. HOTAIR Participation in Glycolysis and Glutaminolysis Through Lactate and Glutamate Production in Colorectal Cancer. Cells 2025; 14:388. [PMID: 40072116 PMCID: PMC11898799 DOI: 10.3390/cells14050388] [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: 01/28/2025] [Revised: 02/21/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025] Open
Abstract
Metabolic reprogramming plays a crucial role in cancer biology and the mechanisms underlying its regulation represent a promising study area. In this regard, the discovery of non-coding RNAs opened a new regulatory landscape, which is in the early stages of investigation. Using a differential expression model of HOTAIR, we evaluated the expression level of metabolic enzymes, as well as the metabolites produced by glycolysis and glutaminolysis. Our results demonstrated the regulatory effect of HOTAIR on the expression of glycolysis and glutaminolysis enzymes in colorectal cancer cells. Specifically, through the overexpression and inhibition of HOTAIR, we determined its influence on the expression of the enzymes PFKFB4, PGK1, LDHA, SLC1A5, GLUD1, and GOT1, which had a direct impact on lactate and glutamate production. These findings indicate that HOTAIR plays a significant role in producing "oncometabolites" essential to maintaining the bioenergetics and biomass necessary for tumor cell survival by regulating glycolysis and glutaminolysis.
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Affiliation(s)
- Laura Cecilia Flores-García
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico; (L.C.F.-G.); (V.G.-C.); (E.P.-T.)
| | - Verónica García-Castillo
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico; (L.C.F.-G.); (V.G.-C.); (E.P.-T.)
| | - Eduardo Pérez-Toledo
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico; (L.C.F.-G.); (V.G.-C.); (E.P.-T.)
| | - Samuel Trujano-Camacho
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando 22, Belisario Domínguez Secc 16, Tlalpan, Mexico City 14080, Mexico; (S.T.-C.); (O.M.-C.); (E.A.P.-Y.); (J.C.-H.)
- Experimental Biology PhD Program, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
| | - Oliver Millán-Catalán
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando 22, Belisario Domínguez Secc 16, Tlalpan, Mexico City 14080, Mexico; (S.T.-C.); (O.M.-C.); (E.A.P.-Y.); (J.C.-H.)
| | - Eloy Andrés Pérez-Yepez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando 22, Belisario Domínguez Secc 16, Tlalpan, Mexico City 14080, Mexico; (S.T.-C.); (O.M.-C.); (E.A.P.-Y.); (J.C.-H.)
| | - Jossimar Coronel-Hernández
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando 22, Belisario Domínguez Secc 16, Tlalpan, Mexico City 14080, Mexico; (S.T.-C.); (O.M.-C.); (E.A.P.-Y.); (J.C.-H.)
| | | | - Nadia Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City 14080, Mexico;
| | - Carlos Pérez-Plasencia
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico; (L.C.F.-G.); (V.G.-C.); (E.P.-T.)
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Av. San Fernando 22, Belisario Domínguez Secc 16, Tlalpan, Mexico City 14080, Mexico; (S.T.-C.); (O.M.-C.); (E.A.P.-Y.); (J.C.-H.)
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4
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Kim JM, Shin HJ, Kim WR, Park EG, Lee DH, Lee YJ, Jeong HS, Roh HY, Kwon HJ, Choi YH, Leem SH, Kim HS. Metformin modulates FJX1 via upregulation of Hsa-miR-1306-3p to suppress colon adenocarcinoma viability. Sci Rep 2025; 15:6658. [PMID: 39994354 PMCID: PMC11850875 DOI: 10.1038/s41598-025-91022-y] [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: 10/29/2024] [Accepted: 02/18/2025] [Indexed: 02/26/2025] Open
Abstract
Metformin, widely used for the treatment of type 2 diabetes, has recently gained attention for its potential anticancer properties. Several studies have shown that metformin treatment inhibits cell viability in colon adenocarcinoma (COAD); however, the research related to the tumor-node-metastasis (TNM) stage is limited. As COAD is frequently diagnosed at an advanced stage, understanding the genetic factors that regulate the pathogenesis of COAD at each TNM stage and the effects of metformin for potential treatment. Therefore, we identified differentially expressed factors at the TNM stage in metformin-treated COAD cells and investigated their regulatory mechanisms using microRNAs (miRNAs). Through bioinformatics analyses, four-jointed box kinase 1 (FJX1) and hsa-miR-1306-3p were identified as differentially expressed in COAD upon metformin treatment. Metformin treatment significantly reduced cell viability, with an observed decrease of approximately 50%. Analysis using quantitative real-time PCR showed an increase in hsa-miR-1306-3p and a decrease in FJX1 expression upon metformin treatment compared to untreated cells. Luciferase assay confirmed the sequence-specific binding of hsa-miR-1306-3p to FJX1. These findings highlight the potential of metformin as a therapeutic agent for COAD by modulating FJX1 expression via upregulation of hsa-miR-1306-3p, revealing novel avenues for COAD treatment.
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Affiliation(s)
- Jung-Min Kim
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hae Jin Shin
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Woo Ryung Kim
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Eun Gyung Park
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Du Hyeong Lee
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Yun Ju Lee
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hyeon-Su Jeong
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Hyun-Young Roh
- Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Ho Jeong Kwon
- Chemical Genomics Leader Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, 47227, Republic of Korea
| | - Sun-Hee Leem
- Department of Biomedical Sciences, Dong-A University, Busan, 49315, Republic of Korea
- Department of Health Sciences, The Graduated of Dong-A University, Busan, 49315, Republic of Korea
| | - Heui-Soo Kim
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea.
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan, 46241, Republic of Korea.
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5
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Olvera-Valencia M, Garcia-Castillo V, Ramos-Payan R, Aguilar-Medina M, Trujano-Camacho S, López-Saavedra A, Marchat LA, López-Camarillo C, Sumagin R, Pérez-Yepez E, Pérez-Plasencia C. Development of a reliable method for human triple-negative breast cancer organotypic culture: Improving imaging and genomic studies in 3D cultures. J Tissue Eng 2025; 16:20417314251326668. [PMID: 40342587 PMCID: PMC12059422 DOI: 10.1177/20417314251326668] [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: 11/08/2024] [Accepted: 02/25/2025] [Indexed: 05/11/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is highly aggressive and lacks targeted therapies, posing a major challenge in oncology. Traditional two-dimensional (2D) cell cultures fail to capture the tumor microenvironment's complexity, whereas three-dimensional (3D) cultures provide a more accurate model of tumor biology. We developed an advanced 3D culture system for TNBC cell lines BT-20 and MDA-MB-231, enhancing the hanging-drop method with Matrigel to restore essential extracellular matrix interactions. Confocal imaging showed MDA-MB-231 cells forming clusters typical of aggressive carcinoma, while BT-20 cells organized into duct-like structures. Molecular analysis of PI3K and β-catenin target genes revealed distinct expression patterns, with PI3K overexpressed and β-catenin downregulated in 3D cultures. Moreover, β-catenin distribution in the 3D cell culture closely resembles its pattern in tissue. These findings underscore the value of 3D models in understanding TNBC progression and in supporting the exploration of novel therapeutic strategies.
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Affiliation(s)
- Mercedes Olvera-Valencia
- Programa Institucional de Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Ticoman, CDMX, Mexico
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, CDMX, Mexico
| | - Verónica Garcia-Castillo
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla Estado de México, Mexico
| | - Rosalío Ramos-Payan
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacan, Sinaloa, Mexico
| | - Maribel Aguilar-Medina
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacan, Sinaloa, Mexico
| | - Samuel Trujano-Camacho
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, CDMX, Mexico
- Experimental Biology PhD Program, DCBS, Universidad Autónoma Metropolitana- Iztapalapa, Iztapalapa, Mexico
| | - Alejandro López-Saavedra
- Advanced Microscopy Applications Unit (ADMIRA)-Instituto Nacional de Cancerología, Tlalpan, CDMX, Mexico
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Laurence A. Marchat
- Programa Institucional de Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, Ticoman, CDMX, Mexico
| | - Cesar López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Benito Juarez, CDMX, Mexico
| | - Ronen Sumagin
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Eloy Pérez-Yepez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, CDMX, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla Estado de México, Mexico
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6
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Stepanov Y, Kolesnik D, Yakshibaeva Y, Solyanik G. EFFECT OF ADHESIVE LLC CELL PRETREATMENT BY OXAMATE ON THE SURVIVAL INDEXES AFTER TRANSITION TO DE-ADHESIVE GROWTH. Exp Oncol 2024; 46:237-243. [PMID: 39704457 DOI: 10.15407/exp-oncology.2024.03.237] [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: 12/19/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND The ability to metabolic reprogramming is a distinctive feature of metastatically active tumor cells. A classic example of metabolic reprogramming, characteristic of almost all malignant cells, is aerobic glycolysis. Therefore, inhibition of glycolysis in tumor cells is considered a promising strategy for antitumor therapy. AIM To generate Lewis lung carcinoma (LLC) cell subpopulation after pretreatment by a lactate dehydrogenase (LDH) inhibitor - oxamate in adhesive growth conditions, and then to study the metabolism of this subpopulation in the anchorage-independent growth conditions. MATERIALS AND METHODS LLC cells were cultured without oxamate or with 17 mM oxamate in the adhesive growth conditions with the following transition to the anchorage-independent growth conditions without oxamate. A distribution of LLC cells by cell cycle phases, apoptosis rate, levels of reactive oxygen species (ROS), E-cadherin, and vimentin were determined by flow cytometry. Glucose consumption and lactate production were determined by spectrophotometry. RESULTS 48-h oxamate treatment in adhesive growth conditions resulted in a 30% decrease of the total number of LLC cells compared to the control. In 72 h after the transfer of both oxamate-treated and control cells into the anchorage-independent growth condition without oxamate, the number of viable cells pretreated with oxamate was reduced by 17% (p < 0.05) compared to the control cells. However, the distribution of cells by cell cycle phases did not differ. In cells pre-treated with oxamate, the rate of glucose consumption decreased by 20% (p < 0.05), ROS generation was reduced by 17%, vimentin expression decreased by 10% while the rate of lactate production was the same in oxamate-pretreated and control cells. CONCLUSION The cytostatic effect of oxamate demonstrated in adhesive growth conditions persisted for 72 h in the anchorage-independent growth conditions. The absence of differences in the cell cycle phase distribution and a decrease in the ROS generation may indicate the initial stage of overcoming the cytostatic effect of oxamate after 72 h of culturing LLC cells in anchorage- independent growth conditions.
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Affiliation(s)
- Yu Stepanov
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - D Kolesnik
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Yu Yakshibaeva
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - G Solyanik
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
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7
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Zhang Y, Wu Y, Liu Z, Yang K, Lin H, Xiong K. Non-coding RNAs as potential targets in metformin therapy for cancer. Cancer Cell Int 2024; 24:333. [PMID: 39354464 PMCID: PMC11445969 DOI: 10.1186/s12935-024-03516-w] [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] [Received: 05/17/2024] [Accepted: 09/24/2024] [Indexed: 10/03/2024] Open
Abstract
Metformin, a widely used oral hypoglycemic drug, has emerged as a potential therapeutic agent for cancer treatment. While initially known for its role in managing diabetes, accumulating evidence suggests that metformin exhibits anticancer properties through various mechanisms. Several cellular or animal experiments have attempted to elucidate the role of non-coding RNA molecules, including microRNAs and long non-coding RNAs, in mediating the anticancer effects of metformin. The present review summarized the current understanding of the mechanisms by which non-coding RNAs modulate the response to metformin in cancer cells. The regulatory roles of non-coding RNAs, particularly miRNAs, in key cellular processes such as cell proliferation, cell death, angiogenesis, metabolism and epigenetics, and how metformin affects these processes are discussed. This review also highlights the role of lncRNAs in cancer types such as lung adenocarcinoma, breast cancer, and renal cancer, and points out the need for further exploration of the mechanisms by which metformin regulates lncRNAs. In addition, the present review explores the potential advantages of metformin-based therapies over direct delivery of ncRNAs, and this review highlights the mechanisms of non-coding RNA regulation when metformin is combined with other therapies. Overall, the present review provides insights into the molecular mechanisms underlying the anticancer effects of metformin mediated by non-coding RNAs, offering novel opportunities for the development of personalized treatment strategies in cancer patients.
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Affiliation(s)
- Yihan Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang, China
| | - Yunhao Wu
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang, China
| | - Zixu Liu
- The First School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Kangping Yang
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang, China
| | - Kai Xiong
- Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China.
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8
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Ugur E, Tidim G, Gundogdu D, Alemdar C, Oral G, Husnugil HH, Banerjee S, Erel-Goktepe I. Effect of Periodate-Induced Cross-linking on Dual Anticancer Drug Release from Poly(2-isopropyl-2-oxazoline)/Tannic Acid-Based Layer-by-Layer Microparticles. ACS OMEGA 2024; 9:39626-39642. [PMID: 39346850 PMCID: PMC11425960 DOI: 10.1021/acsomega.4c03977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 08/09/2024] [Accepted: 08/28/2024] [Indexed: 10/01/2024]
Abstract
This study reports, first, on the preparation and cross-linking of multilayers composed of poly(2-isopropyl-2-oxazoline-co-ethyleneimine) (PiPOX-PEI) and tannic acid (TA). PiPOX was synthesized by cationic ring-opening polymerization (CROP) and partially hydrolyzed, yielding a random copolymer PiPOX-PEI. It was then coassembled at the surface with TA using the layer-by-layer (LbL) technique. Multilayers were exposed to NaIO4 solution to induce covalent bond formation between PEI units of PiPOX-PEI and TA. Cross-linking with NaIO4 enhanced the stability of the multilayers, especially under basic conditions. Second, the potential of PiPOX-PEI and TA multilayers as a stimuli-responsive dual drug-releasing platform was examined using curcumin (CUR) and doxorubicin (DOX) as model drugs. These drugs were chosen as they can act in a combinatorial manner to increase cell death. The surface of CUR-containing CaCO3 microparticles was modified with PiPOX-PEI and TA multilayers and postloaded with DOX. We found that LbL particles could release DOX in a pH-responsive manner, whereas temperature-induced release was observed only when the temperature was raised above 40 °C. The DOX and CUR released from the LbL particles could act synergistically on HCT-116 cells. Cross-linking increased the DOX release from LbL particles but decreased the CUR release from the core. Corroborating the release data, the synergy observed with the non-cross-linked particles was lost with the cross-linked particles, and the decrease in the viability of HCT-116 cells was attributed mainly to the release of DOX. Overall, we describe here NaIO4-induced cross-linking of PiPOX-PEI/TA LbL films, the effects of pH, temperature, and cross-linking on DOX and CUR release from multilayers, and comparison of the combinatorial effect of DOX and CUR for cross-linked and non-cross-linked LbL microparticles through cell viability assays.
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Affiliation(s)
- Esma Ugur
- Department
of Chemistry, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - Gökçe Tidim
- Department
of Chemistry, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - Dilara Gundogdu
- Department
of Chemistry, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - Cemre Alemdar
- Department
of Chemistry, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - Goksu Oral
- Department
of Biology, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - H. Hazal Husnugil
- Department
of Biology, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - Sreeparna Banerjee
- Department
of Biology, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
| | - Irem Erel-Goktepe
- Department
of Chemistry, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
- Center
of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye
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9
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Gonzalez-Gutierrez L, Motiño O, Barriuso D, de la Puente-Aldea J, Alvarez-Frutos L, Kroemer G, Palacios-Ramirez R, Senovilla L. Obesity-Associated Colorectal Cancer. Int J Mol Sci 2024; 25:8836. [PMID: 39201522 PMCID: PMC11354800 DOI: 10.3390/ijms25168836] [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: 07/12/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.
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Affiliation(s)
- Lucia Gonzalez-Gutierrez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Omar Motiño
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Daniel Barriuso
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Juan de la Puente-Aldea
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Lucia Alvarez-Frutos
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006 Paris, France;
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Roberto Palacios-Ramirez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Laura Senovilla
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006 Paris, France;
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
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10
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Fu J, Lin J, Dai Z, Lin B, Zhang J. Hypoxia-associated autophagy flux dysregulation in human cancers. Cancer Lett 2024; 590:216823. [PMID: 38521197 DOI: 10.1016/j.canlet.2024.216823] [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: 02/16/2024] [Revised: 03/09/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024]
Abstract
A general feature of cancer is hypoxia, determined as low oxygen levels. Low oxygen levels may cause cells to alter in ways that contribute to tumor growth and resistance to treatment. Hypoxia leads to variations in cancer cell metabolism, angiogenesis and metastasis. Furthermore, a hypoxic tumor microenvironment might induce immunosuppression. Moreover, hypoxia has the potential to impact cellular processes, such as autophagy. Autophagy refers to the catabolic process by which damaged organelles and toxic macromolecules are broken down. The abnormal activation of autophagy has been extensively recorded in human tumors and it serves as a regulator of cell growth, spread to other parts of the body, and resistance to treatment. There is a correlation between hypoxia and autophagy in human malignancies. Hypoxia can regulate the activity of AMPK, mTOR, Beclin-1, and ATGs to govern autophagy in human malignancies. Furthermore, HIF-1α, serving as an indicator of low oxygen levels, controls the process of autophagy. Hypoxia-induced autophagy has a crucial role in regulating the growth, spread, and resistance to treatment in human malignancies. Hypoxia-induced regulation of autophagy can impact other mechanisms of cell death, such as apoptosis. Chemoresistance and radioresistance have become significant challenges in recent years. Hypoxia-mediated autophagy plays a crucial role in determining the response to these therapeutic treatments.
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Affiliation(s)
- Jiding Fu
- Department of Intensive Care Unit, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Jie Lin
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Zili Dai
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Baisheng Lin
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Jian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
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11
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Kaveh Zenjanab M, Abdolahinia ED, Alizadeh E, Hamishehkar H, Shahbazi R, Ranjbar-Navazi Z, Jahanban-Esfahlan R, Fathi M, Mohammadi SA. Hyaluronic Acid-Targeted Niosomes for Effective Breast Cancer Chemostarvation Therapy. ACS OMEGA 2024; 9:10875-10885. [PMID: 38463340 PMCID: PMC10918778 DOI: 10.1021/acsomega.3c09782] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/29/2024] [Accepted: 02/06/2024] [Indexed: 03/12/2024]
Abstract
Chemotherapy is widely used for cancer therapy; however, its efficacy is limited due to poor targeting specificity and severe side effects. Currently, the next generations of delivery systems with multitasking potential have attracted significant attention for cancer therapy. This study reports on the design and synthesis of a multifunctional nanoplatform based on niosomes (NIO) coloaded with paclitaxel (PTX), a chemotherapeutic drug commonly used to treat breast cancer, and sodium oxamate (SO), a glycolytic inhibitor to enhance the cytotoxicity of anticancer drug, along with quantum dots (QD) as bioimaging agents, and hyaluronic acid (HA) coating for active targeting. HN@QPS nanoparticles with a size of ∼150 nm and a surface charge of -39.9 mV with more than 90% EE for PTX were synthesized. Codelivery of SO with PTX remarkably boosted the anticancer effects of PTX, achieving IC50 values of 1-5 and >0.5 ppm for HN@QP and HN@QPS, respectively. Further, HN@QPS treatment enhanced the apoptosis rate by more than 70% in MCF-7 breast cancer cells without significant cytotoxicity on HHF-2 normal cells. Also, quantification of mitochondrial fluorescence showed efficient toxicity against MCF-7 cells. Moreover, the cellular uptake evaluation demonstrated an improved uptake of HN@Q in MCF-7 cells. Taken together, this preliminary research indicated the potential of HN@QPS as an efficient targeted-dual drug delivery nanotheranostic against breast cancer cells.
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Affiliation(s)
- Masoumeh Kaveh Zenjanab
- Department
of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
- Research
Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
| | - Elaheh Dalir Abdolahinia
- Research
Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
- Department
of Oral Science and Translation Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida 33314, United States
| | - Effat Alizadeh
- Department
of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
| | - Hamed Hamishehkar
- Drug
Applied Research Center, Tabriz University
of Medical Sciences, Tabriz 51656-65931, Iran
| | - Rasoul Shahbazi
- Department
of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
| | - Zahra Ranjbar-Navazi
- Research
Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
| | - Rana Jahanban-Esfahlan
- Department
of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
| | - Marziyeh Fathi
- Research
Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
| | - Seyed Abolghasem Mohammadi
- Department
of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51656-65931, Iran
- Department
of Plant Breeding and Biotechnology, Faculty of Agriculture, University of Tabriz, Tabriz 51666-16471, Iran
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12
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Sinha R, LeVeque RM, Callahan SM, Chatterjee S, Stopnisek N, Kuipel M, Johnson JG, DiRita VJ. Gut metabolite L-lactate supports Campylobacter jejuni population expansion during acute infection. Proc Natl Acad Sci U S A 2024; 121:e2316540120. [PMID: 38170751 PMCID: PMC10786315 DOI: 10.1073/pnas.2316540120] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 11/15/2023] [Indexed: 01/05/2024] Open
Abstract
How the microaerobic pathogen Campylobacter jejuni establishes its niche and expands in the gut lumen during infection is poorly understood. Using 6-wk-old ferrets as a natural disease model, we examined this aspect of C. jejuni pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with C. jejuni, ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after C. jejuni infection in ferrets reflects closely how human C. jejuni infection proceeds. Rapid growth of C. jejuni and associated intestinal inflammation was observed within 2 to 3 d of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A C. jejuni mutant lacking lctP, which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by C. jejuni to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter (lctP) led to identification of a putative thiol-based redox switch regulator (LctR) that may repress lctP transcription under anaerobic conditions. Our work provides better insights into the pathogenicity of C. jejuni.
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Affiliation(s)
- Ritam Sinha
- Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, MI48824
| | - Rhiannon M. LeVeque
- Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, MI48824
| | - Sean M. Callahan
- Department of Microbiology, University of Tennessee, Knoxville, TN37996
| | - Shramana Chatterjee
- Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, MI48824
| | - Nejc Stopnisek
- Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, MI48824
| | - Matti Kuipel
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI48824
| | | | - Victor J. DiRita
- Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, MI48824
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13
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Abstract
Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.
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Affiliation(s)
- Zhi Li
- Cancer Center, First Hospital of Jilin University, Changchun 130021, China
| | - Jiuwei Cui
- Cancer Center, First Hospital of Jilin University, Changchun 130021, China
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14
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Sinha R, LeVeque RM, Callahan SM, Chatterjee S, Stopnisek N, Kuipel M, Johnson JG, DiRita VJ. Gut metabolite L-lactate supports Campylobacter jejuni population expansion during acute infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.02.560557. [PMID: 37873437 PMCID: PMC10592923 DOI: 10.1101/2023.10.02.560557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
How the microaerobic pathogen Campylobacter jejuni establishes its niche and expands in the gut lumen during infection is poorly understood. Using six-week-old ferrets as a natural disease model, we examined this aspect of C. jejuni pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with C. jejuni , ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after C. jejuni infection in ferrets reflects closely how human C. jejuni infection proceeds. Rapid growth of C. jejuni and associated intestinal inflammation was observed within two-three days of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A C. jejuni mutant lacking lctP , which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by C. jejuni to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter ( lctP ) led to discovery of a putative thiol based redox switch regulator (LctR) that may repress lctP transcription under anaerobic conditions. Our work provides new insights into the pathogenicity of C. jejuni . Significance There is a gap in knowledge about the mechanisms by which C. jejuni populations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut after C. jejuni infection. Our study identified the gut metabolite L-lactate as playing an important role as a growth substrate for C. jejuni during acute infection. We identified a DNA binding protein, LctR, that binds to the lctP promoter and may repress lctP expression, resulting in decreased lactate transport under low oxygen levels. This work provides new insights about C. jejuni pathogenicity.
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15
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Siriwaseree J, Yingchutrakul Y, Samutrtai P, Aonbangkhen C, Srathong P, Krobthong S, Choowongkomon K. Exploring the Apoptotic-Induced Biochemical Mechanism of Traditional Thai Herb (Kerra™) Extract in HCT116 Cells Using a Label-Free Proteomics Approach. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1376. [PMID: 37629666 PMCID: PMC10456832 DOI: 10.3390/medicina59081376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023]
Abstract
Background and Objectives: Natural products have proven to be a valuable source for the discovery of new candidate drugs for cancer treatment. This study aims to investigate the potential therapeutic effects of "Kerra™", a natural extract derived from a mixture of nine medicinal plants mentioned in the ancient Thai scripture named the Takxila Scripture, on HCT116 cells. Materials and Methods: In this study, the effect of the Kerra™ extract on cancer cells was assessed through cell viability assays. Apoptotic activity was evaluated by examining the apoptosis characteristic features. A proteomics analysis was conducted to identify proteins and pathways associated with the extract's mechanism of action. The expression levels of apoptotic protein markers were measured to validate the extract's efficacy. Results: The Kerra™ extract demonstrated a dose-dependent inhibitory effect on the cells, with higher concentrations leading to decreased cell viability. Treatment with the extract for 72 h induced characteristic features of early and late apoptosis, as well as cell death. An LC-MS/MS analysis identified a total of 3406 proteins. The pathway analysis revealed that the Kerra™ extract stimulated apoptosis and cell death in colorectal cancer cell lines and suppressed cell proliferation in adenocarcinoma cell lines through the EIF2 signaling pathway. Upstream regulatory proteins, including cyclin-dependent kinase inhibitor 1A (CDKN1A) and MYC proto-oncogene, bHLH transcription factor (MYC), were identified. The expressions of caspase-8 and caspase-9 were significantly elevated by the Kerra™ extract compared to the chemotherapy drug Doxorubicin (Dox). Conclusions: These findings provide strong evidence for the ability of the Kerra™ extract to induce apoptosis in HCT116 colon cancer cells. The extract's efficacy was demonstrated by its dose-dependent inhibitory effect, induction of apoptotic activity, and modulation of key proteins involved in cell death and proliferation pathways. This study highlights the potential of Kerra™ as a promising therapeutic agent in cancer treatment.
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Affiliation(s)
- Jeeraprapa Siriwaseree
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand;
| | - Yodying Yingchutrakul
- National Center for Genetic Engineering and Biotechnology, NSTDA, Pathum Thani 12120, Thailand;
| | - Pawitrabhorn Samutrtai
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Chanat Aonbangkhen
- Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Pussadee Srathong
- Faculty of Nursing, Praboromarajchanok Institute, Nonthaburi 11000, Thailand;
| | - Sucheewin Krobthong
- Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand;
- Interdisciplinary Graduate Program in Genetic Engineering, Kasetsart University, Bangkok 10900, Thailand
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16
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Lai IL, You JF, Tsai WS, Hsu YJ, Chern YJ, Wu MY. Metformin increases pathological responses to rectal cancers with neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. World J Surg Oncol 2023; 21:224. [PMID: 37491250 PMCID: PMC10369710 DOI: 10.1186/s12957-023-03087-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 06/28/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND To summarize the chemo-radio effect of metformin in rectal cancers with neoadjuvant chemoradiotherapy on pathological response, tumor regression grade (TRG), and T/N downstaging. METHODS PubMed, MEDLINE, Embase, and Cochrane Database of collected reviews were searched up to June 30, 2022. This study conducted systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sheet. Odds ratios (ORs) and confidence intervals (CIs) which calculated by random-effects models were displayed in forest plots. Newcastle-Ottawa scale was used to assess the risk of bias of the observational cohort studies. RESULTS This systematic review and meta-analysis comprised eight cohorts out of seven studies, with 2294 patients in total. We performed two-way comparison for metformin in diabetic patients vs (1) non-metformin drugs in diabetic patients and (2) nondiabetic patients. In diabetes patient studies, the metformin group had a significantly increased pathological response on TRG (OR: 3.28, CI: 2.01-5.35, I2 = 0%, p < 0.001) and T downstaging (OR: 2.14, CI: 1.24-3.67, I2 = 14%, p = 0.006) in comparison with a non-metformin group. When compared with nondiabetic patients, the pathological response on TRG (OR: 2.67, CI: 1.65-4.32, I2 = 43%, p < 0.001) and T downstaging (OR: 1.96, CI: 1.04-3.71, I2 = 66%, p = 0.04) were also higher in metformin group. The limitation was that no randomized controlled trials were available based on current literature review. Small sample sizes for diabetic metformin or non-metformin users in rectal cancer patients reduced the power of the study. CONCLUSIONS For patients with rectal cancer and treated with neoadjuvant chemoradiotherapy, metformin administration in diabetic patients increased the pathological response on tumor-regression grade and T downstaging. Further well-designed, high-quality randomized controlled trials are required to reveal the actual effect of metformin.
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Affiliation(s)
- I-Li Lai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1St Rd, Guei-Shan District, Taoyuan City, Taiwan
- Department of SurgeryTen-Chen Medical GroupZhongli Dist., Zhong-Li Metropolitan Hospital, Yanping Rd, No. 155, Taoyuan City, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Wen-Sy Tsai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Yu-Jen Hsu
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Yih-Jong Chern
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Ming-Ying Wu
- Department of Dermatology, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan.
- Institute of Epidemiology and Preventive Medicine, Zhongzheng Dist., National Taiwan University, Xuzhou Rd, No. 17, Taipei City, Taiwan.
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17
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Jin C, Wang T, Yang Y, Zhou P, Li J, Wu W, Lv X, Ma G, Wang A. Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds. ENVIRONMENTAL RESEARCH 2023; 227:115721. [PMID: 36965788 DOI: 10.1016/j.envres.2023.115721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/13/2023] [Accepted: 03/18/2023] [Indexed: 05/08/2023]
Abstract
The abnormal progression of tumors has been a problem for treatment of cancer and therapeutic should be directed towards targeting main mechanisms involved in tumorigenesis in tumors. The genomic mutations can result in changes in biological mechanisms in human cancers. Colorectal cancer is one of the most malignant tumors of gastrointestinal tract and its treatment has been faced some difficulties due to development of resistance in tumor cells and also, their malignant behavior. Hence, new therapeutic modalities for colorectal cancer are being investigated. Autophagy is a "self-digestion" mechanism that is responsible for homeostasis preserving in cells and its aberrant activation/inhibition can lead to tumorigenesis. The current review focuses on the role of autophagy mechanism in colorectal cancer. Autophagy may be associated with increase/decrease in progression of colorectal cancer due to mutual function of this molecular mechanism. Pro-survival autophagy inhibits apoptosis to increase proliferation and survival rate of colorectal tumor cells and it is also involved in cancer metastasis maybe due to EMT induction. In contrast, pro-death autophagy decreases growth and invasion of colorectal tumor cells. The status of autophagy (upregulation and down-regulation) is a determining factor for therapy response in colorectal tumor cells. Therefore, targeting autophagy can increase sensitivity of colorectal tumor cells to chemotherapy and radiotherapy. Interestingly, nanoparticles can be employed for targeting autophagy in cancer therapy and they can both induce/suppress autophagy in tumor cells. Furthermore, autophagy modulators can be embedded in nanostructures in improving tumor suppression and providing cancer immunotherapy.
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Affiliation(s)
- Canhui Jin
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Tianbao Wang
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Yanhui Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China
| | - Pin Zhou
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Juncheng Li
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Wenhao Wu
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Xin Lv
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Guoqing Ma
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Aihong Wang
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China.
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Delgado-Waldo I, Contreras-Romero C, Salazar-Aguilar S, Pessoa J, Mitre-Aguilar I, García-Castillo V, Pérez-Plasencia C, Jacobo-Herrera NJ. A triple-drug combination induces apoptosis in cervical cancer-derived cell lines. Front Oncol 2023; 13:1106667. [PMID: 37223676 PMCID: PMC10200932 DOI: 10.3389/fonc.2023.1106667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/28/2023] [Indexed: 05/25/2023] Open
Abstract
Introduction Cervical cancer is a worldwide health problem due to the number of deaths caused by this neoplasm. In particular, in 2020, 30,000 deaths of this type of tumor were reported in Latin America. Treatments used to manage patients diagnosed in the early stages have excellent results as measured by different clinical outcomes. Existing first-line treatments are not enough to avoid cancer recurrence, progression, or metastasis in locally advanced and advanced stages. Therefore, there is a need to continue with the proposal of new therapies. Drug repositioning is a strategy to explore known medicines as treatments for other diseases. In this scenario, drugs used in other pathologies that have antitumor activity, such as metformin and sodium oxamate, are analyzed. Methods In this research, we combined the drugs metformin and sodium oxamate with doxorubicin (named triple therapy or TT) based on their mechanism of action and previous investigation of our group against three CC cell lines. Results Through flow cytometry, Western blot, and protein microarray experiments, we found TT-induced apoptosis on HeLa, CaSki, and SiHa through the caspase 3 intrinsic pathway, including the critical proapoptotic proteins BAD, BAX, cytochrome-C, and p21. In addition, mTOR and S6K phosphorylated proteins were inhibited in the three cell lines. Also, we show an anti-migratory activity of the TT, suggesting other targets of the drug combination in the late CC stages. Discussion These results, together with our former studies, conclude that TT inhibits the mTOR pathway leading to cell death by apoptosis. Our work provides new evidence of TT against cervical cancer as a promising antineoplastic therapy.
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Affiliation(s)
- Izamary Delgado-Waldo
- Unidad de Bioquímica Guillermo Soberón Acevedo, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México. Copilco Universidad, Coyoacán, Mexico
| | - Carlos Contreras-Romero
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México. Copilco Universidad, Coyoacán, Mexico
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico
| | - Sandra Salazar-Aguilar
- Laboratorio de Hematopoiesis y Leucemia, Unidad de Investigación, Diferenciación Celular y Cáncer, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Iztapalapa, Mexico
| | - João Pessoa
- CNC - Center for Neuroscience and Cell Biology, CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Irma Mitre-Aguilar
- Unidad de Bioquímica Guillermo Soberón Acevedo, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico
| | - Verónica García-Castillo
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
| | - Nadia Judith Jacobo-Herrera
- Unidad de Bioquímica Guillermo Soberón Acevedo, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico
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Qi L, Wang L, Jin M, Jiang M, Li L, Li Y. Caspase-6 is a key regulator of cross-talk signal way in PANoptosis in cancer. Immunology 2023. [PMID: 36814103 DOI: 10.1111/imm.13633] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Cysteinyl aspartate specific proteinase (caspase)-6 belongs to the caspase family and plays a vital role in mediating cell death. Under certain conditions, three pathways of programmed cell death (PCD), including apoptosis, necroptosis and pyroptosis (PANoptosis), transform one way into another, with enormous therapeutic potential. Initially, scholars reported that caspase-6 is a caspase executor that mediates apoptosis. With the ceaseless exploration of the PCD types, studies have demonstrated that caspase-6 mediates pyroptosis by regulating gasdermin D and mediates necroptosis by regulating mixed lineage kinase domain-like. By regulating PANoptosis, caspase-6 plays a crucial role in tumorigenesis in humans and mediates anti-tumour immunity. Therefore, a comprehensive understanding of caspase-6 function in cancer via PANoptosis is important for the prevention and therapy of tumours. This article summarized the function of caspase-6 in PANoptosis and its impact on cancer development, providing targets and strategies for tumour treatment.
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Affiliation(s)
- Ling Qi
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.,Department of Medical Oncology, the Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Li Wang
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Mengru Jin
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.,Department of Medical Oncology, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingxia Jiang
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.,Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lisha Li
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.,Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanjing Li
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
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20
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Olguin JE, Mendoza-Rodriguez MG, Sanchez-Barrera CA, Terrazas LI. Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment? World J Gastrointest Oncol 2023; 15:251-267. [PMID: 36908325 PMCID: PMC9994043 DOI: 10.4251/wjgo.v15.i2.251] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/03/2022] [Accepted: 01/10/2023] [Indexed: 02/14/2023] Open
Abstract
Colorectal cancer (CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence, and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer; thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages III and IV. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors (smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus, the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.
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Affiliation(s)
- Jonadab E Olguin
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
| | - Monica G Mendoza-Rodriguez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
| | - C Angel Sanchez-Barrera
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
| | - Luis I Terrazas
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
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21
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Metformin Alleviates Epirubicin-Induced Endothelial Impairment by Restoring Mitochondrial Homeostasis. Int J Mol Sci 2022; 24:ijms24010343. [PMID: 36613786 PMCID: PMC9820471 DOI: 10.3390/ijms24010343] [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: 10/18/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Vascular endothelial injury is important in anthracycline-induced cardiotoxicity. Anthracyclines seriously damage the mitochondrial function and mitochondrial homeostasis. In this study, we investigated the damage of epirubicin to vascular endothelial cells and the protective role of metformin from the perspective of mitochondrial homeostasis. We found that epirubicin treatment resulted in DNA double-strand breaks (DSB), elevated reactive oxygen species (ROS) production, and excessive Angiotensin II release in HUVEC cells. Pretreatment with metformin significantly mitigated the injuries caused by epirubicin. In addition, inhibited expression of Mitochondrial transcription factor A (TFAM) and increased mitochondria fragmentation were observed in epirubicin-treated cells, which were partially resumed by metformin pretreatment. In epirubicin-treated cells, knockdown of TFAM counteracted the attenuated DSB formation due to metformin pretreatment, and inhibition of mitochondrial fragmentation with Mdivi-1 decreased DSB formation but increased TFAM expression. Furthermore, epirubicin treatment promoted mitochondrial fragmentation by stimulating the expression of Dynamin-1-like protein (DRP1) and inhibiting the expression of Optic atrophy-1(OPA1) and Mitofusin 1(MFN1), which could be partially prevented by metformin. Finally, we found metformin could increase TFAM expression and decrease DRP1 expression in epirubicin-treated HUVEC cells by upregulating the expression of calcineurin/Transcription factor EB (TFEB). Taken together, this study provided evidence that metformin treatment was an effective way to mitigate epirubicin-induced endothelial impairment by maintaining mitochondrial homeostasis.
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22
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Function and regulation of ULK1: From physiology to pathology. Gene 2022; 840:146772. [PMID: 35905845 DOI: 10.1016/j.gene.2022.146772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/03/2022] [Accepted: 07/24/2022] [Indexed: 11/21/2022]
Abstract
The expression of ULK1, a core protein of autophagy, is closely related to autophagic activity. Numerous studies have shown that pathological abnormal expression of ULK1 is associated with various human diseases such as neurological disorders, infections, cardiovascular diseases, liver diseases and cancers. In addition, new advances in the regulation of ULK1 have been identified. Furthermore, targeting ULK1 as a therapeutic strategy for diseases is gaining attention as new corresponding activators or inhibitors are being developed. In this review, we describe the structure and regulation of ULK1 as well as the current targeted activators and inhibitors. Moreover, we highlight the pathological disorders of ULK1 expression and its critical role in human diseases.
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23
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Luo Q, Li X, Gan G, Yang M, Chen X, Chen F. PPT1 Reduction Contributes to Erianin-Induced Growth Inhibition in Oral Squamous Carcinoma Cells. Front Cell Dev Biol 2022; 9:764263. [PMID: 35004674 PMCID: PMC8740138 DOI: 10.3389/fcell.2021.764263] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 12/13/2021] [Indexed: 01/18/2023] Open
Abstract
The anticancer properties of erianin have been recently discovered. However, the antitumor effect of erianin in oral squamous cell carcinoma (OSCC) remains unclear. In this study, we demonstrated that erianin can hamper OSCC cells growth both in vitro and in vivo. Erianin induced obvious G2/M arrest as well as apoptosis and gasdermin E (GSDME)-dependent pyroptosis in OSCC cells. Moreover, erianin increased autophagosome formation but decreased autolysosome function. Further study indicated that erianin significantly suppressed the expression of protein-palmitoyl thioesterase 1 (PPT1) and mTOR signaling. PPT1 has been reported to be a critical regulator of cancer progression by its modulation of autophagy and mTOR signaling. According to online databases, higher expression of PPT1 has been observed in OSCC tissues and is associated with poorer patient prognosis. As overexpression of PPT1 significantly reversed erianin-induced growth inhibition in OSCC cells, we identified the importance of PPT1 reduction in erianin-induced growth suppression. With the xenograft model, we confirmed the antitumor effect of erianin in vivo. Erianin efficiently decreased the tumor sizes, together with visibly reduced expression of PPT1 and phosphorylation of mTOR in the xenograft tumor tissues. Therefore, the present study indicated that erianin may be potentially used in OSCC therapy.
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Affiliation(s)
- Qingqiong Luo
- Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Li
- Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guifang Gan
- Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng Yang
- Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Chen
- Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuxiang Chen
- Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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24
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Wang Z, Hao D, Fang D, Yu J, Wang X, Qin G. Transcriptome Analysis Reveal Candidate Genes and Pathways Responses to Lactate Dehydrogenase Inhibition (Oxamate) in Hyperglycemic Human Renal Proximal Epithelial Tubular Cells. Front Endocrinol (Lausanne) 2022; 13:785605. [PMID: 35370938 PMCID: PMC8970056 DOI: 10.3389/fendo.2022.785605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 02/21/2022] [Indexed: 11/24/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of both chronic kidney disease (CKD) and end-stage renal disease (ESRD). Previous studies showed that oxamate could regulate glycemic homeostasis and impacted mitochondria respiration in a hyperglycemia-dependent manner in the rat proximal tubular cells. To explore the transcriptome gene expression profiling of kidney tissues in human renal proximal epithelial tubular cell line (HK-2), we treated HK-2 cells with high D-glucose (HG) for 7 days before the addition of 40 mM oxamate for a further 24 hours in the presence of HG in this study. Afterwards, we identified 3,884 differentially expressed (DE) genes based on adjusted P-value ≤ 0.05 and investigated gene relationships based on weighted gene co-expression network analysis (WGCNA). After qRT-PCR validations, MAP1LC3A, MAP1LC3B (P-value < 0.01) and BECN1 were found to show relatively higher expression levels in the treated groups than the control groups, while PGC1α (P-value < 0.05) showed the lower expressions. Accordingly, enrichment analyses of GO terms and KEGG pathways showed that several pathways [e.g., lysosome pathway (hsa04142) and p53 signaling pathway (hsa04115)] may be involved in the response of HK-2 cells to oxamate. Moreover, via WGCNA, we identified two modules: both the turquoise and blue modules were enriched in pathways associated with lysosome. However, the p53 signaling pathway was only found using all 3,884 DE genes. Furthermore, the key hub genes IGFBP3 (adjusted P-value = 1.34×10-75 and log2(FC) = 2.64) interacted with 6 up-regulated and 12 down-regulated DE genes in the network that were enriched in the p53 signaling pathway. This is the first study reporting co-expression patterns of a gene network after lactate dehydrogenase inhibition in HK-2 cells. Our results may contribute to our understanding of the underlying molecular mechanism of in vitro reprogramming under hyperglycemic stress that orchestrates the survival and functions of HK-2 cells.
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Affiliation(s)
- Zhimin Wang
- Division of Endocrinology and Metabolic Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dan Hao
- Shaanxi Key Laboratory of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Dong Fang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, Beijing, China
| | - Jiating Yu
- Division of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao Wang
- Konge Larsen ApS, Kongens Lyngby, Denmark
- *Correspondence: Xiao Wang, ; Guijun Qin,
| | - Guijun Qin
- Division of Endocrinology and Metabolic Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Xiao Wang, ; Guijun Qin,
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25
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Wang WM, Yang SS, Shao SH, Nie HQ, Zhang J, Su T. Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma. Front Endocrinol (Lausanne) 2022; 13:828608. [PMID: 35222283 PMCID: PMC8864766 DOI: 10.3389/fendo.2022.828608] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/10/2022] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Type 2 diabetes mellitus (T2DM) is among the risk factors for the occurrence and development of cancer. Metformin is a potential anticancer drug. Epidermal growth factor receptor (EGFR) plays an important role in the progression of oral squamous cell carcinoma(OSCC), but the relationship between metformin and EGFR expression in OSCC remains unclear. METHODS This study involved the immunohistochemical detection of EGFR expression in cancer tissues of patients with T2DM and OSCC. The patients were divided into groups according to whether they were taking metformin for the treatment of T2DM, and the expression of EGFR in different groups was compared. Correlation analysis between the expression of EGFR and the fluctuation value of fasting blood glucose (FBG) was carried out. Immunohistochemistry was used to detect the expression of EGFR in cancer tissues of patients with recurrent OSCC. These patients had normal blood glucose and took metformin for a long time after the first operation. RESULTS EGFR expression in T2DM patients with OSCC taking metformin was significantly lower than that in the non-metformin group. FBG fluctuations were positively correlated with the expression of EGFR in the OSCC tissues of the non-metformin group of T2DM patients. In patients with recurrent OSCC with normal blood glucose, metformin remarkably reduced the expression of EGFR in recurrent OSCC tissues. CONCLUSION Metformin may regulate the expression of EGFR in a way that does not rely on lowering blood glucose. These results may provide further evidence for metformin in the treatment of OSCC.
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Affiliation(s)
- Wei-Ming Wang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Si-Si Yang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
| | - Shu-Hui Shao
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
| | - Huan-Quan Nie
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Zhang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Tong Su
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
- *Correspondence: Tong Su,
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Arinno A, Maneechote C, Khuanjing T, Ongnok B, Prathumsap N, Chunchai T, Arunsak B, Kerdphoo S, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N. Cardioprotective effects of melatonin and metformin against doxorubicin-induced cardiotoxicity in rats are through preserving mitochondrial function and dynamics. Biochem Pharmacol 2021; 192:114743. [PMID: 34453902 DOI: 10.1016/j.bcp.2021.114743] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 01/23/2023]
Abstract
Doxorubicin (Dox) is widely used in chemotherapy regimens for several malignant conditions. Unfortunately, cumulative and irreversible cardiotoxicity of Dox is the most prominent adverse effect which limits its use. Several pharmacological interventions which exert antioxidant properties, including melatonin and metformin, have demonstrated beneficial effects against various cardiac pathological conditions. However, the exact molecular mechanisms underlying their cardioprotective effects are not completely understood. We hypothesized that treatment with either melatonin or metformin provides cardioprotection against Dox-induced cardiotoxicity through mitochondrial protection. Thirty-two male Wistar rats received 6 doses of either 0.9% normal saline solution (0.9% NSS, n = 8) or Dox (3 mg/kg, i.p., n = 24). The Dox-treated rats (n = 8/group) were co-treated with: 1) Vehicle (0.9% NSS), 2) Melatonin (10 mg/kg/day), and 3) Metformin (250 mg/kg/day) for 30 consecutive days via oral gavage. Following the treatment, left ventricular (LV) function, oxidative stress, inflammation, mitochondrial function, dynamics, biogenesis and bioenergetics, mitophagy, autophagy, and apoptosis were determined. Dox induced excessive oxidative stress, inflammation, autophagy, apoptosis, reduced mitochondrial function, dynamics balance, biogenesis, and bioenergetics leading to LV dysfunction. Treatment with either melatonin or metformin exerted equal measures of cardioprotection via reducing oxidative stress, inflammation, autophagy, apoptosis, and improved mitochondrial function, dynamics balance, biogenesis, and bioenergetics in the Dox-treated rats. Melatonin and metformin exerted both anti-cancer and cardioprotective properties, suggesting they have potential roles in concomitant therapy in cancer patients receiving Dox treatment.
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Affiliation(s)
- Apiwan Arinno
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Thawatchai Khuanjing
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Benjamin Ongnok
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nanthip Prathumsap
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Titikorn Chunchai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Busarin Arunsak
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sasiwan Kerdphoo
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Krekwit Shinlapawittayatorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
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