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Chen RY, Liu YJ, Wang R, Yu J, Shi JJ, Yang GJ, Chen J. Fingerprint of ubiquitin coupled enzyme UBC13 in health and disease. Bioorg Chem 2025; 161:108524. [PMID: 40319811 DOI: 10.1016/j.bioorg.2025.108524] [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: 01/27/2025] [Revised: 04/16/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
Ubiquitination is one of the most well-known post-translational modifications in eukaryotes. UBC13 is an E2 ubiquitin coupling enzyme, which interacts with different E3 ligases and exerts ubiquitination activity to assemble and synthesize lysine-63-linked (Lys63) ubiquitin strands, thus playing an important role in cell homeostasis, various diseases caused by inflammation, and the occurrence and development of cancer. In this paper, we review the structure and function of UBC13, summarize the diverse pathways it mediates, and discuss its involvement in bacterial and non-bacterial inflammatory diseases. Additionally, we explore UBC13's role in physiological damage repair mechanisms, cancer development, DNA damage repair, immune cell maturation, and function. Furthermore, We also elucidate the progress of the discovery of small molecule inhibitors targeting UBC13 and summarize their structure, which suggests that targeting UBC13 may be a potential disease treatment strategy.
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Affiliation(s)
- Ru-Yi Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China
| | - Yan-Jun Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China
| | - Ran Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China
| | - Jing Yu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China
| | - Jin-Jin Shi
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China.
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211, Zhejiang, China.
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Altiparmak-Ulbegi G, Hasbal-Celikok G, Aksoy-Sagirli P. AKT1 and CTNNB1 mutations as drivers of paclitaxel resistance in breast cancer cells. Oncol Lett 2025; 30:324. [PMID: 40370645 PMCID: PMC12076040 DOI: 10.3892/ol.2025.15070] [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: 12/19/2024] [Accepted: 03/26/2025] [Indexed: 05/16/2025] Open
Abstract
Breast cancer (BC) is the most prevalent cancer type in the world, with increasing incidence rates. Drug resistance is a notable factor that limits the effectiveness of BC therapy. Paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane class, is commonly used in BC; however, its efficacy is often compromised by drug resistance, which is primarily attributed to genetic alterations. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and wingless-type MMTV integration site family/β-catenin signaling pathways are involved in essential cellular processes, such as proliferation, apoptosis and maintenance of homeostasis. Dysregulated activation of these pathways is strongly associated with carcinogenesis and drug resistance. In the present study, the potential effects of AKT1 (E17K/E49K/L52R) and catenin β-1 (CTNNB1; S33P/T41A/S45F) mutations on PTX resistance in BC were investigated in vitro using site-directed mutagenesis, transient transfection, MTS assay and western blot analyses. The results of the present study indicated that AKT1-E17K/E49K and CTNNB1-S45F/T41A mutations induced PTX resistance compared with AKT1-wild-type (WT) and CTNNB1-WT in MCF-7 cells, respectively. In MDA-MB-231 cells, all three AKT1 mutations (E17K/E49K/L52R) triggered PTX resistance compared with AKT1-WT, while none of the CTNNB1 mutations exhibited such an effect. In conclusion, AKT1 mutations may serve as a biomarker for PTX resistance in both estrogen receptor (ER)(+)/progesterone receptor (PR)(+)/HER2(-) and triple negative BC, while CTNNB1 mutations may be a potential biomarker for PTX resistance in ER(+)/PR(+)/HER2(-) BC.
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Affiliation(s)
| | - Gozde Hasbal-Celikok
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
| | - Pinar Aksoy-Sagirli
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
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Xing Q, Li W, Chen J, Liu Z, Hu Y, Li W, Liu X, Xiao C. Screening the absorbed active components of Danggui Sini Decoction in the treatment of diabetic peripheral neuropathy by network pharmacology combined with molecular docking and dynamics simulation. J Biomol Struct Dyn 2025:1-14. [PMID: 40382779 DOI: 10.1080/07391102.2025.2505251] [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: 02/04/2024] [Accepted: 05/21/2024] [Indexed: 05/20/2025]
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent and detrimental condition that can be debilitating and even fatal if not treated; however, there remains a dearth of efficacious pharmaceutical interventions for DPN. The Danggui Sini Decoction (DSD), a renowned traditional Chinese medicine prescription, has been utilized in the clinic for the treatment of DPN because of its efficacy in addressing yang deficiency and cold coagulation. However, the active components and underlying mechanisms of DSD remain unclear. In this study, we devised a conventional approach to screen the absorbed active ingredients in DSD, employing LC-MS to identify the principal active compounds of DSD in the blood of rats and then validating these components using network pharmacology for target prediction and molecular dynamics simulations for further validation. We identified 17 potentially active components in the serum and 47 main targets that might be relevant for treating DPN with DSD. These targets were associated with pathways including neuroactive ligand-receptor interaction, HIF-1, and AGE-RAGE signaling pathways, all of which are implicated in diabetic complications. Through molecular docking, we found that glycyrrhetinic acid and betulonic acid-two active components identified by LC-MS in the DSD-containing serum of rats-exhibited strong binding activities with AKT1 and STAT3. Furthermore, molecular dynamics simulations of the docking results indicated that the AKT1-glycyrrhetinic acid and AKT1-betulonic acid complexes were highly stable throughout the kinetic simulations. These findings suggest that the molecular mechanism underlying DSD treatment of DPN may involve the activation of AKT1 by glycyrrhetinic acid and betulonic acid.
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Affiliation(s)
- Qichang Xing
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Wei Li
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
| | | | - Zheng Liu
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
| | - Yixiang Hu
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
| | - Wencan Li
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
| | - Xiang Liu
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Can Xiao
- Clinical pharmacy, Xiangtan Central Hospital, Xiangtan, China
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Zu GX, Tang JQ, Huang HL, Han T. Validation and analysis of key factors of Banxia Xiexin decoction against gastric cancer. World J Gastrointest Oncol 2025; 17:104737. [DOI: 10.4251/wjgo.v17.i5.104737] [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: 12/31/2024] [Revised: 01/14/2025] [Accepted: 03/04/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND In China Banxia Xiexin decoction (BXD) has been used in treating gastric cancer (GC) for thousands of years. BXD has been shown to reverse GC histopathology, but its chemical composition and action mechanism are still unknown.
AIM To investigate the mechanism of BXD against GC based on utilizing transcriptomics and proteomics techniques experiments.
METHODS Using the AGS cell line as the model group, the Cell Counting Kit-8 method and Annexin V-AbFluor™ were employed 488/propidium iodide double staining method was used to detect the levels of cell proliferation and apoptosis. Differential expression genes and differentially expressed proteins before and after BXD intervention were detected using RNA-seq and Pro DIA techniques. Key transcription factors were identified by enrichment and analysis using Metascape, and the key pathways were validated by western blot and reverse transcription PCR in vitro and in vivo experiments.
RESULTS BXD significantly inhibited the proliferation rate and migration rate of GC cells and promoted cell apoptosis. The comprehensive analysis of transcriptomics and proteomics showed that five transcription factors, namely phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, phosphoinositide-3-kinase regulatory subunit 1, AKT serine/threonine kinase 1, heat shock protein 90 alpha family class A member 1, and tumor protein p53, were key factors in BXD-mediated anti-cancer therapy and participated in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. In vitro experiments were conducted using LY294002, an inhibitor of the PI3K/AKT signaling pathway, to validate the expression of five transcription factors at the protein and mRNA levels. In vivo experiments have shown that BXD inhibits tumor growth and suppresses the expression of the PI3K/AKT signaling pathway.
CONCLUSION Transcriptomic and proteomic analysis showed that BXD inhibited tumor growth and slowed cancer progression by suppressing five factors in the PI3K/AKT signaling pathway, including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, phosphoinositide-3-kinase regulatory subunit 1, and AKT serine/threonine kinase 1.
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Affiliation(s)
- Guo-Xiu Zu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Ji-Qin Tang
- School of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Hai-Liang Huang
- School of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Tao Han
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
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Sun J, Yang D, Huang Y, Jiao Z, Yu S, Liu Y, Gong K, Zhao G. The discovery of novel N-heterocyclic-based AKT inhibitors with potential efficacy against prostate cancer. Eur J Med Chem 2025; 289:117435. [PMID: 40020427 DOI: 10.1016/j.ejmech.2025.117435] [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: 11/06/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/03/2025]
Abstract
AKT, a serine/threonine protein kinase that plays a pivotal role in the PI3K/AKT/mTOR pathway, is overexpressed or hyperactivated in various cancers, including prostate, breast, and lung cancers. A series of novel nitrogen-containing aromatic heterocyclic compounds were designed, synthesized, and evaluated for AKT inhibition and anticancer activities. Among these, JL16 and JL18 emerged as potent inhibitors of AKT1 kinase, with IC50 values of 7.1 ± 1.2 nM and 8.8 ± 1.3 nM, respectively. Both compounds also demonstrated significant antiproliferative effects against PC-3 prostate cancer cells, with IC50 values of 2.9 ± 0.7 μM (JL16) and 3.0 ± 0.6 μM (JL18). Mechanistic studies revealed that JL16 and JL18 reduced phosphorylated GSK3β levels, confirming AKT target engagement in cells. Notably, JL18 exhibited favorable pharmacokinetic properties in mice, including rapid oral absorption (Tmax = 0.5 h) and 41 % bioavailability. These findings highlight JL16 and JL18 as promising AKT inhibitors for further preclinical development.
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Affiliation(s)
- Jinxiao Sun
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Dezhi Yang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Yongmi Huang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Zhihao Jiao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Shangzhe Yu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Yiru Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Kexin Gong
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Guisen Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China.
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Bardaweel SK, Jaradat E, Hajjo R, AlJarrah H. Unraveling the Anticancer Potential of SSRIs in Prostate Cancer by Combining Computational Systems Biology and In Vitro Analyses. ACS OMEGA 2025; 10:15204-15218. [PMID: 40290959 PMCID: PMC12019733 DOI: 10.1021/acsomega.4c10939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/19/2025] [Accepted: 04/03/2025] [Indexed: 04/30/2025]
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are known to have anticancer activity against different types of cancer. In this study, an integrative informatics approach was applied to identify compound and genetic perturbations that produce similar effects to SSRIs to formulate systems biology hypotheses and identify biological pathways involved in the putative anticancer effects of SSRIs in prostate cancer. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay assessed the antiproliferative effects of SSRIs and drug combinations. Cell death mechanisms were studied using annexin V-FITC/PI staining, and the cell cycle analysis was carried out by counterstaining with propidium iodide. Relative gene expression was assessed using a real-time polymerase chain reaction (PCR). Computational results hypothesized that SSRIs could potentially exert anticancer effects in prostate cancer cell lines by modulating apoptotic and tumorigenesis pathways and significantly inhibiting the growth of prostate cancer cells in a time and concentration-dependent manner. The combination of SSRIs with cisplatin, 5-fluorouracil, and raloxifene resulted in either synergistic or additive effects. SSRIs resulted in a significant increase in the early and late apoptotic activity in PC3 cells. Dapoxetine, paroxetine, and sertraline resulted in cell cycle arrest at the G0/G1 phase. Treatment with either dapoxetine or paroxetine decreases the expression of Bcl-2, CASP8, DR5, and VEGF. At the same time, sertraline decreases the expression of Bcl-2 and VEGF and increases the expression of CASP8 and DR5. Results revealed that SSRIs can potentially act as antiproliferative agents against prostate cancer cells, and their activity is mediated through different signaling pathways.
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Affiliation(s)
- Sanaa K. Bardaweel
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Esraa Jaradat
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Rima Hajjo
- Department
of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah
University of Jordan, P.O. Box 130, Amman 11733, Jordan
- Laboratory
for Molecular Modeling, Division of Chemical Biology and Medicinal
Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-5023, United
States
- Board
Member, Jordan CDC, Amman 11183, Jordan
| | - Hashem AlJarrah
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
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Mandal M, Banerjee I, Mandal M. Effective approaches in conquering chemoresistance of glioblastoma: potential for nanoformulations. Drug Deliv Transl Res 2025:10.1007/s13346-025-01859-z. [PMID: 40259195 DOI: 10.1007/s13346-025-01859-z] [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: 04/10/2025] [Indexed: 04/23/2025]
Abstract
Glioblastoma Multiforme is an aggressive and complex cancer affecting mostly elderly patients above the age of 60 years. Originally classified as the fourth stage of glioma, it has an abysmal prognosis along with limited therapeutic options. Surgical removal of tumors, radiotherapy, and chemotherapy are prevalent treatment strategies with numerous therapeutic obstacles, including undefined boundary of tumor mass leaving traces even after excision, chances of secondary cancer formation, and presence of blood-brain barrier. These blood-brain and blood-brain tumor barriers actively restrict the permeability of many molecules from blood circulation to enter the central nervous system. Therefore, many conventional antineoplastic drugs fail to reach the tumor periphery except temozolomide. Meanwhile, active stem cells in the tumor microenvironment, genetic mutation inducing tumor growth, and epigenetic pattern alteration make this cancer chemoresistant. Our review delineates the recent approaches to resensitize the existing clinical drugs through specifically designed nanoformulations. Nanoparticles with modified physiological characteristics and modified through technological parameters can reduce the tumor's stemness, which increases tumor cells' apoptosis rate. Moreover, these nanoparticles can efficiently traverse the blood-brain barrier and escape from endosomal degradation with minimum toxicological impact. Overall, this review discusses the cancer chemoresistance phenomena and related pathways and highlights the potential of nanoformulation in reversing chemoresistance. Also, the existing limitations of this unique approach and suggestions are discussed at the end of the article, which may facilitate the identification of new directions for advancement of the nanoparticle-mediated reversal of chemoresistance.
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Affiliation(s)
- Madhurima Mandal
- School of Medical Science & Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India
| | - Indranil Banerjee
- Department of Pharmaceutical Technology, JIS University, 81, Nilgunj Road, Agarpara, Kolkata, West Bengal, 700109, India.
| | - Mahitosh Mandal
- School of Medical Science & Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
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Wu Z, Zhang G, Shang Y, Huang J, Liu Y, Zhou H, Wang T. New curcumin derivative induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis. Bioorg Med Chem 2025; 121:118078. [PMID: 39965986 DOI: 10.1016/j.bmc.2025.118078] [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: 11/13/2024] [Revised: 12/28/2024] [Accepted: 01/14/2025] [Indexed: 02/20/2025]
Abstract
Previous experiments have revealed that curcumin exerts potential antitumor effect by inducing apoptosis and ferroptosis of tumor cells. However, its low solubility and bioavailability, as well as fast metabolism limit its clinical use. The structural modification of curcumin is beneficial for the discovery of potential candidate drugs for cancer treatment. Here, three new series of curcumin derivatives including 25 compounds were synthesized at active sites on benzene ring and β-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) in vitro showed that compound 4a-4e displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound 4d is particularly prominent against MCF-7, with IC50 of 1.39 μM. Preliminary mechanism found that compound 4d could trigger ferrous ions and ROS accumulation, increase MDA level in MCF-7 cells, while significantly down-regulate GPX4 level in dose-dependent manner. Western Blot results discovered that compound 4d decreased the ratio of SLC7A11 to GAPDH and GPX4 to β-actin. Docking results indicated that compound 4d had good binding affinity to the active site of GPX4 (PDB ID: 7u4n and 7u4k). In conclusion, compound 4d may be potential anti-tumor agent, which induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.
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Affiliation(s)
- Zhiwen Wu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, People's Republic of China
| | - Guoqiang Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, People's Republic of China
| | - Yifan Shang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, People's Republic of China
| | - Jiaxin Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, People's Republic of China
| | - Yongqian Liu
- Department of Pharmacy, Guangdong Maternal and Child Health Hospital, Guangzhou 511400, Guangdong, People's Republic of China
| | - Huixian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, People's Republic of China; Department of Pharmaceutical Equipment, Yangchun Hospital of Traditional Chinese Medicine, Yangchun 529600, Guangdong, People's Republic of China.
| | - Tao Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, People's Republic of China.
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Adon T, Bhattacharya S, Madhunapantula SV, Kumar HY. Structural requirements of isoform-specific inhibitors of Akt: Implications in the development of effective cancer treatment strategies. Eur J Med Chem 2025; 287:117334. [PMID: 39904143 DOI: 10.1016/j.ejmech.2025.117334] [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: 10/30/2024] [Revised: 12/18/2024] [Accepted: 01/25/2025] [Indexed: 02/06/2025]
Abstract
Akt, also known as protein kinase-B, is an important therapeutic target in the treatment of cancer due to its pivotal roles in the signaling pathways that regulate various hall-mark features of cancer cells such as cell growth, survival, migration, differentiation, and metabolism. The three closely related isoforms of Akt viz., Akt1, Akt2, and Akt3 exhibit distinct physiological roles that affect cellular behavior and tumor development, making isoform selectivity a crucial driving factor in the design and development of inhibitors. This review outlines key amino acids and their structural traits in Akt isoforms, potentially dictating isoform selectivity. We present an analysis of existing structure-activity relationship data of covalent-allosteric Akt inhibitors to shed light on isoform selectivity. Additionally, a brief review of potential predictive biomarkers in enhancing the therapeutic efficacy of Akt inhibitors is presented. Identifying biomarkers that can reliably predict patient response to treatment is crucial for personalizing cancer therapies and improving overall treatment outcomes. By integrating predictive biomarker identification with the ongoing development of isoform-selective Akt inhibitors, it is plausible to establish a foundation for more precise and efficacious interventions in cancer therapy.
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Affiliation(s)
- Tenzin Adon
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India; Computer Aided Drug Design Lab, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India
| | - Sanyukta Bhattacharya
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India; Computer Aided Drug Design Lab, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India
| | - SubbaRao V Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR, A DST-FIST Supported Center and ICMR-Collaborating Center of Excellence), Department of Biochemistry (A DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India; Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India; University Sophisticated Instrumentation Centre (USIC) [Supported by DST-PURSE & DBT-BUILDER], JSS Academy of Higher Education & Research (JSS AHER), Mysuru, 570015, Karnataka, India
| | - Honnavalli Yogish Kumar
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India; Computer Aided Drug Design Lab, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India; University Sophisticated Instrumentation Centre (USIC) [Supported by DST-PURSE & DBT-BUILDER], JSS Academy of Higher Education & Research (JSS AHER), Mysuru, 570015, Karnataka, India.
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10
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Jiang S, Li C, Liu D, Zeng F, Wei W, He T, Yang W. Role, mechanisms and effects of Radix Bupleuri in anti‑breast cancer (Review). Oncol Lett 2025; 29:166. [PMID: 39963320 PMCID: PMC11831725 DOI: 10.3892/ol.2025.14912] [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: 10/02/2024] [Accepted: 12/30/2024] [Indexed: 02/20/2025] Open
Abstract
The prevalence of breast cancer among women has led to a growing need for innovative anti-breast cancer medications and an in-depth investigation into their molecular mechanisms of action, both of which are essential tactics in clinical intervention. In the clinical practice of Traditional Chinese Medicine, Radix Bupleuri and its active components have shown promise as potential anti-breast cancer agents due to their ability to target multiple pathways, exhibit synergistic effects and reduce toxicity. These compounds are considered to enhance the prognosis of patients with cancer, prolong survival and combat chemotherapy resistance. The present review aimed to delve into the anti-breast cancer properties of Radix Bupleuri and its active ingredients, highlighting their mechanisms, such as inhibition of cell proliferation, promotion of apoptosis, metastasis prevention, microenvironment improvement and synergy with certain chemotherapeutic agents. These findings may provide a scientific rationale for combining Radix Bupleuri and its active components with traditional chemotherapy agents for the management of breast cancer.
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Affiliation(s)
- Shiting Jiang
- Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Chengxia Li
- Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Dan Liu
- Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Fancai Zeng
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Wenli Wei
- Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Tao He
- Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Wenli Yang
- Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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Xu X, Fu J, Yang G, Chen Z, Chen S, Yuan G. Dentin sialoprotein promotes endothelial differentiation of dental pulp stem cells through DSP aa34-50-endoglin-AKT1 axis. J Biol Chem 2025; 301:108380. [PMID: 40049415 PMCID: PMC11997338 DOI: 10.1016/j.jbc.2025.108380] [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: 08/15/2024] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 04/01/2025] Open
Abstract
Dentin sialoprotein (DSP), a major dentin extracellular matrix noncollagenous protein, is well recognized as an important regulator for dentinogenesis. DSP as a secreted protein can interact with membrane receptors, activate intracellular signaling, and initiate the odontoblastic differentiation of dental papilla cells. In a recent study, we have demonstrated that DSP can induce the endothelial differentiation of dental pulp stem cells (DPSCs), a type of tooth pulp-derived multipotent stem cells, dependent on membrane receptor endoglin (ENG). However, the intimate mechanisms by which DSP-ENG association facilitates the endothelial differentiation of DPSCs remain enigmatic. Here, we find that the amino acid (aa) residues 34-50 of DSP (DSPaa34-50) is responsible for its association with ENG using a series of co-immunoprecipitation assays. Immunofluorescent staining and in situ proximity ligation assay demonstrate that overexpressed ENG in human embryonic kidney 293T cells shows codistribution and proximity ligation assay signals to the supplemented DSPaa34-50 protein but not to DSP without aa34-50 (DSPΔ34-50) on cell surfaces. Moreover, the zona pellucida domain of ENG mediates its association with DSPaa34-50. Further experiments indicate that DSPaa34-50 exhibits equivalent effects to the full-length DSP on the migration and endothelial differentiation of DPSCs dependent on ENG but DSPΔ34-50 does not. Mechanistically, DSPaa34-50 activates AKT1 and triggers the expression of blood vessel development-related genes in DPSCs. Multiple experiments demonstrate that AKT1 inhibition suppresses the DSPaa34-50-induced migration and endothelial differentiation of DPSCs. Thus, AKT1 mediates the cellular and molecular functions of DSPaa34-50-ENG association. Collectively, these findings identify that DSP promotes the endothelial differentiation of DPSCs through the DSPaa34-50-ENG-AKT1 signaling axis.
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Affiliation(s)
- Ximin Xu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
| | - Jing Fu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
| | - Guobin Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Zhi Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Shuo Chen
- Department of Developmental Dentistry, School of Dentistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Guohua Yuan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China.
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12
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Zhang W, Bradburn D, Heidebrink G, Liu Y, Jang H, Nussinov R, Kõivomägi M. Distinct Allosteric Networks in CDK4 and CDK6 in the Cell Cycle and in Drug Resistance. J Mol Biol 2025:169121. [PMID: 40174666 DOI: 10.1016/j.jmb.2025.169121] [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: 01/31/2025] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/04/2025]
Abstract
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) are key regulators of the G1-S phase transition in the cell cycle. In cancer cells, CDK6 overexpression often outcompetes CDK4 in driving cell cycle progression, contributing to resistance against CDK4/6 inhibitors (CDK4/6i). This suggests distinct functional and conformational differences between these two kinases, despite their striking structural and sequence similarities. Understanding the mechanisms that differentiate CDK4 and CDK6 is crucial, as resistance to CDK4/6i-frequently linked to CDK6 overexpression-remains a significant therapeutic challenge. Notably, CDK6 is often upregulated in CDK4/6i-resistant cancers and rapidly proliferating hematopoietic stem cells, underscoring its unique regulatory roles. We hypothesize that their distinct conformational dynamics explain their differences in phosphorylation of retinoblastoma protein, Rb, inhibitor efficacy, and cell cycle control. This leads us to question how their dissimilar conformational dynamics encode their distinct actions. To elucidate their differential activities, molecular mechanisms, and inhibitor binding, we combine biochemical assays and molecular dynamics (MD) simulations. We discover that CDK4 and CDK6 have distinct allosteric networks connecting the β3-αC loop and the G-loop. CDK6 exhibits stronger coupling and shorter path lengths between these regions, resulting in higher kinase activity upon cyclin binding and impacting inhibitor specificity. We also discover an unrecognized role of the unstructured CDK6 C-terminus, which allosterically connects and stabilizes the R-spine, facilitating slightly higher activity. Our findings bridge the gap between the structural similarity and functional divergence of CDK4 and CDK6, advancing the understanding of kinase regulation in cancer biology.
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Affiliation(s)
- Wengang Zhang
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
| | - Devin Bradburn
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA
| | - Gretchen Heidebrink
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA
| | - Yonglan Liu
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
| | - Hyunbum Jang
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA; Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Ruth Nussinov
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA; Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
| | - Mardo Kõivomägi
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA.
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13
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Shah H, Khan K, Badshah Y, Trembley JH, Ashraf NM, Shabbir M, Afsar T, Aldisi D, Khan D, Razak S. Unravelling the role of PRKCI and key-cancer related genes in breast cancer development and metastasis. Discov Oncol 2025; 16:350. [PMID: 40100546 PMCID: PMC11920535 DOI: 10.1007/s12672-025-02133-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 03/12/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Breast cancer is one of the most common causes of fatalities in females globally. Rising cases of drug resistance against existing chemotherapeutics are great problem. To address this issue, there is a need to find appropriate biomarker that could be used to detect cancer at early stages, so drug resistance development can be avoided. Protein Kinase C iota (PKCɩ), an AGC kinase, has an oncogenic role in cancers and its expression and Single nucleotide polymorphisms (SNPs) have been reported to be associated with the cancer development. So, the study aims were to examine the expression of PKCɩ, Protein Kinase B (AKT), Suppressor of cytokine signaling 3 (SOCS3), Vascular endothelial growth factor (VEGF), Krupple like factor 3 (KLF3), Tumor protein D52 (TPD52), Hypoxia inducible factor (HIF1α) and microRNA-124 (miR-124) in breast cancer and association of PKCɩ variants (G34W & F66Y) with breast cancer. METHODS Genetic expression assay was performed through real time Polymerase Chain reaction (PCR), whereas the genotypic association of PKCɩ SNPs with breast cancer was accomplished through Tetra-ARMS PCR. RESULTS The expression levels of PKCɩ, AKT, SOC3, VEGF, HIF1α and TPD52 were elevated in patients as compared to control whereas the expression levels of miR-124 and KLF3 were lowered in patients. Positive association of variant G34W (TT) of PKCɩ with breast cancer has been explored through ARM's PCR, while no association of variant F66Y with breast cancer was found. CONCLUSION Hence, the results suggest that PKCɩ and related genes can have a role in breast cancer and after further verification can serve as the potential biomarkers for the early-diagnosis and prognosis of breast cancer.
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Affiliation(s)
- Hania Shah
- Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Yasmin Badshah
- Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Janeen H Trembley
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
- Minneapolis VA Health Care System Research Service, Minneapolis, MN, USA
| | - Naeem Mahmood Ashraf
- Department of Biochemistry and Biotechnology, University of Punjab, Lahore, Pakistan
| | - Maria Shabbir
- Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Tayyaba Afsar
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Dara Aldisi
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Dilawer Khan
- Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Suhail Razak
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
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14
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Luo K, Wu Q, Li Z, Wu Y, Su Z, Zhou F, Li Q, Ren B, Li Y, Li J, Peng X. Cyclic di-AMP alleviates periodontitis by activating PI3K/Akt/Nrf2 pathways. Front Cell Infect Microbiol 2025; 15:1560155. [PMID: 40160469 PMCID: PMC11949975 DOI: 10.3389/fcimb.2025.1560155] [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: 01/14/2025] [Accepted: 02/26/2025] [Indexed: 04/02/2025] Open
Abstract
Emerging research demonstrates the regulatory effects of c-di-AMP, a bacterial-derived small molecule secondary messenger, on host immune responses and promoting resistance against infection-related diseases. This study aims to elucidate the role of c-di-AMP in the occurrence and development of periodontitis. Using model of ligation-induced periodontitis, we observed that c-di-AMP effectively alleviated alveolar bone resorption. Transcriptomic sequencing in mice gingival tissues demonstrated that treatment with c-di-AMP led to a significant upregulation of the PI3K/Akt signaling pathway and its key components, including Akt3. Concurrently, we observed an upregulation of the cGMP/PKG signaling pathway. To validate our findings, we treated gingival epithelial cells with c-di-AMP and confirmed the activation of the PI3K/Akt pathway by c-di-AMP in gingival epithelial cells. Under LPS-induced inflammation, c-di-AMP significantly suppressed the release of inflammatory factors (such as IL-6 and TNF-α) from gingival epithelial cells. Moreover, key components of the PI3K/Akt pathway, including Akt, and downstream inflammation regulatory gene Nrf2, were upregulated, which were also confirmed at the protein level. Collectively, this study demonstrates that c-di-AMP definitely plays a role in alleviating periodontitis. Our findings highlight the mechanisms by which c-di-AMP modulates periodontitis, including activating the PI3K/Akt pathway and potentially involving the cGMP/PKG pathway, ultimately contributing to improved immune defense and maintenance of bone homeostasis.
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Affiliation(s)
- Kaihua Luo
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Qinrui Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhengyi Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yajie Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhifei Su
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Fangjie Zhou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Qinyang Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Biao Ren
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yuqing Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jiyao Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xian Peng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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15
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Valdivia-Padilla AV, Sharma A, Zegbe JA, Morales-Domínguez JF. Metabolomic Characterization and Bioinformatic Studies of Bioactive Compounds in Two Varieties of Psidium guajava L. Leaf by GC-MS Analysis. Int J Mol Sci 2025; 26:2530. [PMID: 40141181 PMCID: PMC11942350 DOI: 10.3390/ijms26062530] [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: 02/14/2025] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
The guava tree (Psidium guajava L.) is a tropical plant from the Myrtaceae family. Leaf extracts from this plant have been used in traditional medicine to treat gastrointestinal disorders and exhibit several functional activities that benefit human health. Different varieties of guava trees produce fruits in colors ranging from white to red and present a characteristic metabolic profile in both their leaves and fruits. This study presents a metabolomic characterization of the leaves from two guava varieties: the Caxcana cultivar with yellow fruits and the S-56 accession with pink fruits. Metabolite profiling was conducted using Gas Chromatography-Mass Spectrometry (GC-MS) on methanol extracts, followed by multivariate statistical analysis, including Principal Component Analysis (PCA), and a heat map visualization of compound concentrations in the two varieties. The results identified β-caryophyllene as the major secondary metabolite present in both varieties, with a relative abundance of 16.46% in the Caxcana variety and 23.06% in the S-56 cultivar. Furthermore, in silico analyses, such as network pharmacology and molecular docking, revealed key interactions with proteins such as CB2, PPARα, BAX, BCL2, and AKT1, suggesting potential therapeutic relevance. These findings highlight the pharmacological potential of guava leaf metabolites in natural product chemistry and drug discovery.
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Affiliation(s)
- Ana Victoria Valdivia-Padilla
- Centro de Ciencias Básicas, Departamento de Química, Universidad Autónoma de Aguascalientes, Aguascalientes 20131, Mexico;
| | - Ashutosh Sharma
- Centre of Bioengineering, NatProLab, School of Engineering and Sciences, Tecnologico de Monterrey, Querétaro 76130, Mexico;
| | - Jorge A. Zegbe
- Campo Experimental Pabellón, Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias, Km 32.5 Carretera Aguascalientes-Zacatecas, Pabellón de Arteaga, Aguascalientes 20668, Mexico;
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16
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Zhang W, Bradburn D, Heidebrink G, Liu Y, Jang H, Nussinov R, Kõivomägi M. Distinct allosteric networks in CDK4 and CDK6 in the cell cycle and in drug resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.28.640857. [PMID: 40093074 PMCID: PMC11908124 DOI: 10.1101/2025.02.28.640857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) are key regulators of the G1-S phase transition in the cell cycle. In cancer cells, CDK6 overexpression often outcompetes CDK4 in driving cell cycle progression, contributing to resistance against CDK4/6 inhibitors (CDK4/6i). This suggests distinct functional and conformational differences between these two kinases, despite their striking structural and sequence similarities. Understanding the mechanisms that differentiate CDK4 and CDK6 is crucial, as resistance to CDK4/6i-frequently linked to CDK6 overexpression-remains a significant therapeutic challenge. Notably, CDK6 is often upregulated in CDK4/6i-resistant cancers and rapidly proliferating hematopoietic stem cells, underscoring its unique regulatory roles. We hypothesize that their distinct conformational dynamics explain their differences in phosphorylation of retinoblastoma protein, Rb, inhibitor efficacy, and cell cycle control. This leads us to question how their dissimilar conformational dynamics encode their distinct actions. To elucidate their differential activities, molecular mechanisms, and inhibitor binding, we combine biochemical assays and molecular dynamics (MD) simulations. We discover that CDK4 and CDK6 have distinct allosteric networks connecting the β3-αC loop and the G-loop. CDK6 exhibits stronger coupling and shorter path lengths between these regions, resulting in higher kinase activity upon cyclin binding and impacting inhibitor specificity. We also discover an unrecognized role of the unstructured CDK6 C-terminus, which allosterically connects and stabilizes the R-spine, facilitating slightly higher activity. Our findings bridge the gap between the structural similarity and functional divergence of CDK4 and CDK6, advancing the understanding of kinase regulation in cancer biology.
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Affiliation(s)
- Wengang Zhang
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, U.S.A
| | - Devin Bradburn
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, U.S.A
| | - Gretchen Heidebrink
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, U.S.A
| | - Yonglan Liu
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, U.S.A
| | - Hyunbum Jang
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, U.S.A
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, U.S.A
| | - Ruth Nussinov
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, U.S.A
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, U.S.A
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Mardo Kõivomägi
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD 20892, U.S.A
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17
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Duraisamy R, Veerasamy V, Balakrishnan V, Jawaharlal S, Subramani S, Sathiavakoo VA. Exploring anticancer potential of betanin in DMBA-induced oral squamous cell carcinoma: an in silico and experimental study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03909-2. [PMID: 40009172 DOI: 10.1007/s00210-025-03909-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
In addition to being able to fight cancer, betanin (BTN) has amazing natural antioxidant and peroxy-radical scavenging properties. 7,12-Dimethylbenz[a]anthracene (DMBA) can impair the activities of enzymes accountable for breaking down xenobiotics and can also cause lipid peroxidation. The study's goal was to find out if betanin could protect against these problems. We determined 100% tumor incidence, abnormal tumor volume, inclined tumor burden, and deduced body weight in DMBA-induced hamsters. We observed diminished lipid peroxidation and enzymatic and nonenzymatic antioxidant activities in DMBA-induced hamsters. The histological study showed that the hamster that receives only DMBA undergoes hyperkeratosis, epithelial hyperplasia, dysplasia, and well-differentiated oral squamous cell carcinoma (OSCC). The hamsters received three different dosages of BTN (10, 20, and 40 mg/kg b.w.) via intragastric intubation for 14 weeks, on alternate days of DMBA painting. The levels of antioxidants, xenobiotic enzymes, and lipid peroxidation (LPO) were significantly restored and inhibited tumor development in a dose-dependent manner. The molecular docking study found high levels of binding affinity in Bax (PDB ID: 2K7W), Caspase-3 (PDB ID: 4JJ8), Caspase-9 (PDB ID: 2AR9), PI3K (PDB ID: 5XGI), AKT (PDB ID: 6BUU), p53 (PDB ID: 1YCS), SMAD-2 (PDB ID: 1DEV), SMAD-4 (PDB ID: 1YGS), SMAD-7 (PDB ID: 2DJY), TGFβ-I (PDB ID: 1PY5), and TGFβ-II (PDB ID: 1M9Z). So, therefore, in vivo and in silico studies were providing prominent anticancer activity of betanin against DMBA-induced oral cancer.
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Affiliation(s)
- Ramachandhiran Duraisamy
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Annamalainagar, 608002, Tamil Nadu, India
| | - Vinothkumar Veerasamy
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Annamalainagar, 608002, Tamil Nadu, India.
| | - Vaitheeswari Balakrishnan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Annamalainagar, 608002, Tamil Nadu, India
| | - Saranya Jawaharlal
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Annamalainagar, 608002, Tamil Nadu, India
| | - Srinivasan Subramani
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Annamalainagar, 608002, Tamil Nadu, India
- Research Department of Biochemistry, Government Arts College for Women, Krishnagiri, Tamil Nadu, India
| | - Vigil Anbiah Sathiavakoo
- Central Animal House Government Medical College and Hospital Cuddalore, Chidambaram, Annamalainagar, 608002, Tamil Nadu, India
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18
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Wang Y, Zheng X, Yang Y, Zhao X, Li M, Huang J, Zhang Q, Qin X, Yu Y, Pan Q, Cao Z. Effect of the CSFV NS5A protein on key proteins in the MAPK and PI3K-mTOR signaling pathways in porcine macrophages. Front Microbiol 2025; 16:1559840. [PMID: 40078537 PMCID: PMC11897277 DOI: 10.3389/fmicb.2025.1559840] [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: 01/13/2025] [Accepted: 02/11/2025] [Indexed: 03/14/2025] Open
Abstract
Classical swine fever (CSF) is a highly contagious disease caused by classical swine fever virus (CSFV). NS5A, a non-structural protein of CSFV, plays an important role in regulating viral replication and protein translation. The purpose of this study was to investigate the effects of the CSFV NS5A protein on key proteins in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) pathways in porcine macrophages. In this study, an NS5A lentivirus was constructed, and 3D4/21 cells were infected. The cells infected for 48 h were collected for proteomic analysis to screen the differential proteins in the two signaling pathways in the NS5A/control group, and the expression levels of key proteins were verified by Western blotting (Wb). CSFV NS5A lentivirus was successfully constructed and used to infect porcine macrophages, and 23 upregulated proteins and 16 downregulated proteins were found in the MAPK signaling pathway, whereas 5 upregulated and 15 downregulated proteins were found in the PI3K-mTOR signaling pathway. The results revealed that with increasing infection time, the expression of IKBKG, AKT1, CDC37, MAP3K2, and PKN2 decreased, whereas the expression of MAP3K7 and KRAS2 increased. The 3D4/21 cells infected with NS5A lentivirus and classical swine fever virus were inoculated, and the differential protein expression was verified via Wb. With increasing time, the protein expression levels of IKBKG and KRAS2 increased, whereas the protein expression levels of MAP3K7, MAP3K2, AKT1, CDC37, and PKN2 decreased. This study provides data for revealing the mechanism by which CSFV evades host antiviral immune clearance and has important scientific significance and potential application value.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ying Yu
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Qing Pan
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Zhi Cao
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
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19
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Zhao P, Zhang Y, Yu Y, Zhang Q, Liu X, Zhang XD, Chen S, de Bock CE, Thorne RF, Shi Y. FAT1 functions as an oncogenic driver in triple negative breast cancer through AKT pathway-driven effects on the matrisome. Int J Biol Sci 2025; 21:2201-2222. [PMID: 40083689 PMCID: PMC11900804 DOI: 10.7150/ijbs.104921] [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: 10/09/2024] [Accepted: 01/17/2025] [Indexed: 03/16/2025] Open
Abstract
FAT1 cadherin exhibits dual tumor suppressor and oncogenic roles across various cancers, but its function in breast cancer remains unclear due to conflicting reports of mutational loss and overexpression. In this study, we demonstrate that FAT1 mRNA and protein levels are reduced during mammary transformation, an effect linked to promoter methylation rather than mutational events. Subtype-specific analysis reveals that high FAT1 expression correlates with poor outcomes in basal-like/triple-negative breast cancer (TNBC), while elevated FAT1 expression in luminal A/estrogen receptor-positive breast cancers is associated with improved patient prognosis. Functional studies in TNBC models using knockdown and overexpression approaches confirm that FAT1 promotes both cell proliferation and motility. High-throughput sequencing and biochemical assessments establish strong links between FAT1 phenotypes and the activation of PI3K-AKT signaling. Additionally, FAT1 manipulation induces significant changes in matrisome-related genes, extracellular matrix components, and integrin switching. Together, these findings define an oncogenic role for FAT1 in TNBC, providing mechanistic insights into how its regulation influences AKT signaling, cell proliferation, and motility.
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Affiliation(s)
- Panpan Zhao
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Yuanyuan Zhang
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Yang Yu
- Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan Province, 450003, China
| | - Qing Zhang
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Xiaoying Liu
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Xu Dong Zhang
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Song Chen
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Charles E. de Bock
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Rick F. Thorne
- Translational Research Institute, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China
| | - Yujie Shi
- Department of Pathology, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450000, Henan, China
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20
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Salem MM, Gerges MN, Abd El Salam HA, Noser AA. New thiadiazolopyrimidine-ornamented pyrazolones as prospective anticancer candidates via suppressing VEGFR-2/PI3K/Akt signaling pathway: Synthesis, characterization, in-silico, and in-vitro studies. Int J Biol Macromol 2025; 289:138735. [PMID: 39689791 DOI: 10.1016/j.ijbiomac.2024.138735] [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: 11/12/2024] [Revised: 12/07/2024] [Accepted: 12/11/2024] [Indexed: 12/19/2024]
Abstract
New thiadiazolopyrimidine-ornamented pyrazolones (4a-8b) have been synthesized by a cyclocondensation reaction of 3a, b with different active methylene compounds. The structure of our products was confirmed via different physical and spectroscopic data. We assessed all newly thiadiazolopyrimidine-ornamented pyrazolones' potential to inhibit angiogenesis, metastasis, and cancer growth by utilizing in-silico investigations focused on the VEGFR-2 signaling pathway and elucidate their pharmacokinetic features using ADMET. Based on our results, compound 8b was chosen for in vitro evaluation since it had the highest binding energy of -10.252 kcal/mol using molecular docking. Compound 8b significantly damaged the T47D (IC50 = 33.01 ± 2.2 μM) cells, without any toxic effect on normal cells in comparison to chemotheraputic FDA approved drug cisplatin (Cis) (IC50 = 3.163 ± 1.7 μM). Additionally, compound 8b significantly suppressed the VEGFR-2 receptor protein that triggers the inhibition of PI3K/Akt genes which causes mitochondrial membrane malfunction resulting in Bax overexpression and Bcl-2 downregulation levels. Besides, compound 8b showed a notable decrease in the levels of nitric oxide (NO) production levels and arrested the cell cycle in the G0/G1 stage. These outcomes demonstrated that compound 8b adhered to Lipinski's rules and may serve as a potential candidate for future breast cancer treatments via obstructing the VEGFR-2/PI3K/Akt signaling pathway, which in turn prevents metastasis, angiogenesis, and proliferation.
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Affiliation(s)
- Maha M Salem
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt.
| | - Marian N Gerges
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt.
| | - Hayam A Abd El Salam
- Green Chemistry Department, National Research Centre, Dokki, Giza 12622, Cairo, Egypt
| | - Ahmed A Noser
- Organic Chemistry, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt.
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21
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Asnaghi R, Antonarelli G, Battaiotto E, Castellano G, Guidi L, Izzo D, Zagami P, Trapani D, Curigliano G. An update on promising and emerging protein kinase B/AKT inhibitors for breast cancer. Expert Opin Pharmacother 2025; 26:235-247. [PMID: 39846444 DOI: 10.1080/14656566.2025.2454290] [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: 11/07/2024] [Revised: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 01/24/2025]
Abstract
INTRODUCTION The PI3K pathway is crucial in breast cancer (BC), influencing cell survival, growth, and metabolism, with AKT playing a central role in treatment resistance. This pathway's involvement in breast carcinogenesis and its link to treatment resistance underscores the significance of targeting it in BC therapy. PI3K-pathway inhibitors offer new therapeutic avenues but bring challenges, especially due to toxicity issues that hinder their development. AREAS COVERED This review discusses the PI3K-pathway inhibitors used in BC, highlighting emerging, innovative strategies. EXPERT OPINION The introduction of mTOR inhibitors marked a key step in tackling hormone receptor-positive (HR+) BC, targeting endocrine resistance. However, toxicity concerns remain, especially with PIK3CA and AKT inhibitors. Selective PI3K-targeted agents aim to reduce off-target toxicity, enhancing patient adherence and control over the disease. New compounds employing allosteric mechanisms may further limit adverse effects and allow safer combination therapies, previously limited by toxicity. Advancements in dosing strategies focus on patient-centered outcomes, and synergistic agents are essential in advancing AKT-pathway inhibition, paving the way for a new phase in HR+ BC treatment.
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Affiliation(s)
- Riccardo Asnaghi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Elena Battaiotto
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Grazia Castellano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Lorenzo Guidi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Davide Izzo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Paola Zagami
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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22
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Malarz K, Borzęcka W, Ziola P, Domiński A, Rawicka P, Bialik-Wąs K, Kurcok P, Torres T, Mrozek-Wilczkiewicz A. pH-sensitive phthalocyanine-loaded polymeric nanoparticles as a novel treatment strategy for breast cancer. Bioorg Chem 2025; 155:108127. [PMID: 39798455 DOI: 10.1016/j.bioorg.2025.108127] [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: 09/17/2024] [Revised: 12/15/2024] [Accepted: 01/01/2025] [Indexed: 01/15/2025]
Abstract
Novel pH-sensitive polymeric photosensitizer carriers from the phthalocyanine (Pc) group were investigated as potential photodynamic therapy drugs for the treatment of breast cancer. Their high antiproliferative activity was confirmed by photocytotoxicity studies, which indicated their high efficacy and specificity toward the SK-BR-3 cell line. Importantly, the Pcs encapsulated in the polymeric nanoparticle (NP) carrier exhibited a much better penetration into the acidic environment of tumor cells than their free form. The investigated Pc4-NPs and TT1-NPs exhibited a high selectivity to healthy fibroblasts as well as non-toxicity without irradiation. This paper describes the detailed mechanism of action of the evaluated compounds by measuring reactive oxygen species (ROS), including singlet oxygen; imaging cellular localization; and analyzing key signaling pathway proteins. An additional advantage of the evaluated compounds is their ability to inhibit the Akt protein expression, including its phosphorylation, which the Western blot test confirmed. This is particularly important because breast cancers often overexpress the HER-2 receptor-related signaling proteins. Moreover, an analysis of proteins such as GLUT-1, HO-1, phospho-p42/44, and BID revealed the significant involvement of ROS in disrupting cellular homeostasis, thereby leading to the induction of oxidative stress and resulting in apoptotic cell death.
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Affiliation(s)
- Katarzyna Malarz
- Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland; A. Chełkowski Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland
| | - Wioleta Borzęcka
- Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Marii Skłodowskiej-Curie 34, 41-819 Zabrze, Poland.
| | - Patryk Ziola
- A. Chełkowski Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland
| | - Adrian Domiński
- Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Marii Skłodowskiej-Curie 34, 41-819 Zabrze, Poland
| | - Patrycja Rawicka
- A. Chełkowski Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland
| | - Katarzyna Bialik-Wąs
- Department of Chemistry and Technology of Polymers, Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24, 31-155 Cracow, Poland
| | - Piotr Kurcok
- Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Marii Skłodowskiej-Curie 34, 41-819 Zabrze, Poland
| | - Tomas Torres
- Department of Organic Chemistry, Autonoma University of Madrid, 28049 Madrid, Spain; IMDEA-Nanociencia, Campus de Cantoblanco, c/Faraday 9, 28049 Madrid, Spain; Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
| | - Anna Mrozek-Wilczkiewicz
- Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland; A. Chełkowski Institute of Physics, University of Silesia in Katowice, 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland.
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23
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Pavithran A, Matarese M, Morone B, Filograna A, Monte ML, Dathan NA, Corda D, Grimaldi G. PARP12-mediated ADP-ribosylation contributes to breast cancer cell fate by regulating AKT activation and DNA-damage response. Cell Mol Life Sci 2025; 82:58. [PMID: 39847113 PMCID: PMC11757654 DOI: 10.1007/s00018-025-05586-z] [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: 03/28/2024] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 01/30/2025]
Abstract
Breast cancer represents the primary cause of death of women under 65 in developed countries, due to the acquisition of multiple drug resistance mechanisms. The PI3K/AKT pathway is one of the major regulating mechanisms altered during the development of endocrine resistance and inhibition of steps in this signalling pathway are adopted as a key strategy to overcome this issue. ADP-ribosylation is a post-translational modification catalysed by PARP enzymes that regulates essential cellular processes, often altered in diseases. PARP12, a member of this family, has been associated with the onset of drug resistance in oestrogen receptor-positive breast cancers, making this enzyme a promising drug target. The molecular basis underlying its involvement in the acquisition of resistance are unknown to date. Here, we demonstrate that PARP12-mediated mono-ADP-ribosylation of AKT is required for AKT activation whilst the absence of PARP12 leads to apoptosis induction in a subset of oestrogen receptor-positive breast cancer cells. Our data show that transcriptional inhibition of PARP12 correlates with an increased DNA-damage induction, mirrored by augmented p53 nuclear localisation and enhanced p53-AKT interaction. Under these conditions, AKT is functionally incompetent towards its downstream targets FOXO, hence favouring cell death. This is achieved by increasing protein levels of the FOXO1 transcription factor, that in turn activates the apoptotic cascade. Overall, we show a novel regulation step of AKT activation and apoptosis relying on PARP12-mediated mono-ADP-ribosylation and propose PARP12 as a potential pharmacological target to be exploited as an innovative therapeutical strategy to overcome endocrine resistance.
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Affiliation(s)
- Anupama Pavithran
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
- OU Health Stephenson Cancer Center, Oklahoma, USA
| | - Maria Matarese
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
| | - Barbara Morone
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
| | - Angela Filograna
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
| | - Matteo Lo Monte
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
| | - Nina Alayne Dathan
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
| | - Daniela Corda
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy
| | - Giovanna Grimaldi
- Institute of Endotypes in Oncology, Metabolism, and Immunology, National Research Council, Via Pietro Castellino 111, Naples, Italy.
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24
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Hao L, Fragoso-Saavedra M, Liu Q. Upregulation of porcine epidemic diarrhea virus (PEDV) RNA translation by the nucleocapsid protein. Virology 2025; 602:110306. [PMID: 39603168 DOI: 10.1016/j.virol.2024.110306] [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: 07/25/2024] [Revised: 10/17/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024]
Abstract
The role of coronaviral nucleocapsid (N) protein in regulating viral translation remains poorly understood. Here, we showed that the N protein of porcine epidemic diarrhea virus (PEDV) enhances the translation of both virus-like genomic RNA (gRNA) and messenger RNA. Further characterization of the gRNA translation upregulation showed that the N-terminal domain (NTD) + Linker region plays a major role. The stem-loop 1 in the 5' untranslated region (UTR) and the budged stem loop in the 3'UTR are required for viral translation upregulation by PEDV N protein. The signaling kinase Akt exists in three isoforms. We found that Akt1 enhances viral gRNA translation upregulation by the N protein dependent on its kinase activity. We further showed an interaction between Akt1 and PEDV N, that is abolished by the NTD + Linker region. This suggested that the enhancing effect of Akt1 on translation upregulation by the N protein does not require interaction between these two proteins.
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Affiliation(s)
- Lin Hao
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Vaccinology and Immunotherapeutics, School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Mario Fragoso-Saavedra
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Vaccinology and Immunotherapeutics, School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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25
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Debnath A, Mazumder R. Clinical Progress of Targeted Therapy for Breast Cancer: A Comprehensive Review. Curr Cancer Drug Targets 2025; 25:555-573. [PMID: 38566384 DOI: 10.2174/0115680096289260240311062343] [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: 10/31/2023] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 04/04/2024]
Abstract
The discovery of effective breast cancer therapy is both urgent and daunting, beset by a myriad of challenges that range from the disease's inherent heterogeneity to its complex molecular underpinnings. Drug resistance, the intricacies of the tumor microenvironment, and patient-specific variables further complicate this landscape. The stakes are even higher when dealing with subtypes like triple-negative breast cancer, which eludes targeted hormonal therapies due to its lack of estrogen, progesterone, and HER2 receptors. Strategies to overcome such challenges include combinations of drugs and identifying new drug targets. Developing new drugs based on such targets could be a better solution than relying on costly immunotherapy or combinational therapies. In this review, we have endeavored to comprehensively examine the proven therapeutic drug targets associated with breast cancer and elucidate their respective molecular mechanisms and current clinical status. This study aims to facilitate researchers in conducting a comparative analysis of different targets to select single and multi-targeted drug discovery approaches for breast cancer.
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Affiliation(s)
- Abhijit Debnath
- Noida Institute of Engineering and Technology (Pharmacy Institute), 19 Knowledge Park-II, Institutional Area, Greater Noida, 201306, Uttar Pradesh, India
| | - Rupa Mazumder
- Noida Institute of Engineering and Technology (Pharmacy Institute), 19 Knowledge Park-II, Institutional Area, Greater Noida, 201306, Uttar Pradesh, India
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26
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Ilango S, K. G, Kulothungan VK. Molecular docking analysis of pyrrole derivatives with different breast cancer targets. Bioinformation 2024; 20:1890-1898. [PMID: 40230904 PMCID: PMC11993369 DOI: 10.6026/9732063002001890] [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: 12/01/2024] [Revised: 12/31/2024] [Accepted: 12/31/2024] [Indexed: 04/16/2025] Open
Abstract
Breast cancer is major risk of death in women. Hence, it is interest to document the molecular docking analysis of SR9009 (a pyrrole derivatives) with different breast cancer target protein targets such as HER2, Erα, PR, PI3K, AKT, Reverbα, BRMS1, Aromatase and mTOR, CDK4, CDK6, TK and Top II. Among 13 proteins, HER2, Erα, Aromatase, Reverbα, BRMS1 and Top II have good binding score affinity. Molecular Dynamic results show that significant higher binding energy for Reverb alpha + SR9009 complex found to be -220.618 +/- 19.145 kJ/mol compared to Reverb alpha + Doxorubicin complex found to be -154.812 +/- 18.235 kJ/mol. Molecular docking and dynamics analysis show that SR9009 is a potential drug candidate targeting Reverb alpha for anti-breast cancer activity.
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Affiliation(s)
- Stephen Ilango
- Department of Pharmaceutical Chemistry, Mother Theresea Post Graduate and Research Institute of Health Sciences (Government of Puducherry Institution), Gorimedu, Puducherry - 605006, India
| | - Girija K.
- Department of Pharmaceutical Chemistry, Mother Theresea Post Graduate and Research Institute of Health Sciences (Government of Puducherry Institution), Gorimedu, Puducherry - 605006, India
| | - Vasantha Kumar Kulothungan
- Department of Bioinformatics, Pondicherry University (Central University), Chinna kalapet, Puducherry 605014, India
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27
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Liu L, Graff SL, Wang Y. New Emerging Therapies Targeting PI3K/AKT/mTOR/PTEN Pathway in Hormonal Receptor-Positive and HER2-Negative Breast Cancer-Current State and Molecular Pathology Perspective. Cancers (Basel) 2024; 17:16. [PMID: 39796647 PMCID: PMC11718791 DOI: 10.3390/cancers17010016] [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: 11/08/2024] [Revised: 12/17/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
In hormone receptor-positive and HER2-negative breast cancers, a growing number of revolutionary personalized therapies are in clinical use or trials, such as CDK4/6 inhibitors, immune checkpoint inhibitors, and PIK3CA inhibitors. Those treatment options are largely driven by the presence or absence of genomic alterations in the tumor. Therefore, molecular profiling is often performed during disease progression. The most encountered genomic alterations are in the PI3K/AKT/mTOR/PTEN pathway. This review discusses the genetic alterations associated with the PI3K/AKT/mTOR/PTEN pathway to help clinicians understand drug selection, resistance, or interaction from a molecular pathologist's perspective.
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Affiliation(s)
- Liu Liu
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Brown University Health, Providence, RI 02903, USA;
- Legorreta Cancer Center, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
| | - Stephanie L. Graff
- Legorreta Cancer Center, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
- Division of Medical Oncology, Rhode Island Hospital and Brown University Health, Providence, RI 02903, USA
| | - Yihong Wang
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Brown University Health, Providence, RI 02903, USA;
- Legorreta Cancer Center, Warren Alpert School of Medicine, Brown University, Providence, RI 02903, USA;
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28
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Arner EN, Alzhanova D, Westcott JM, Hinz S, Tiron CE, Blø M, Mai A, Virtakoivu R, Phinney N, Nord S, Aguilera KY, Rizvi A, Toombs JE, Reese TC, Fey V, Micklem D, Gausdal G, Ivaska J, Lorens JB, Brekken RA. AXL-TBK1 driven AKT3 activation promotes metastasis. Sci Signal 2024; 17:eado6057. [PMID: 39689180 DOI: 10.1126/scisignal.ado6057] [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: 02/27/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024]
Abstract
The receptor tyrosine kinase AXL promotes tumor progression, metastasis, and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we found that activation of AXL resulted in the phosphorylation of TANK-binding kinase 1 (TBK1) and the downstream activation of AKT3 and Snail, a transcription factor critical for EMT. Mechanistically, we showed that TBK1 directly bound to and phosphorylated AKT3 in a manner dependent on the multiprotein complex mTORC1. Upon activation, AKT3 interacted with and promoted the nuclear accumulation of Snail, which led to increased EMT as assessed by marker abundance. In human pancreatic ductal adenocarcinoma tissue, nuclear AKT3 colocalized with Snail and correlated with worse clinical outcomes. Primary mouse pancreatic cancer cells deficient in AKT3 showed reduced metastatic spread in vivo, suggesting selective AKT3 inhibition as a potential therapeutic avenue for targeting EMT in aggressive cancers.
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Affiliation(s)
- Emily N Arner
- Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Dina Alzhanova
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jill M Westcott
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Stefan Hinz
- Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- BerGenBio ASA, Bergen, Norway
| | - Crina Elena Tiron
- Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- Regional Institute of Oncology, Iasi, Romania
| | | | | | - Reetta Virtakoivu
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
- Department of Life Technologies, University of Turku, 20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Natalie Phinney
- Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Silje Nord
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | | | - Ali Rizvi
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jason E Toombs
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tanner C Reese
- Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Vidal Fey
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
- Department of Life Technologies, University of Turku, 20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | | | | | - Johanna Ivaska
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
- Department of Life Technologies, University of Turku, 20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - James B Lorens
- Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
| | - Rolf A Brekken
- Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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29
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Yan W, Chen C, Zheng Y, Xu J, Wang Y, He X. Total triterpenoids from apple peels exert pronounced anti-breast-cancer activity in vivo and in vitro. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:9228-9239. [PMID: 39007208 DOI: 10.1002/jsfa.13745] [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: 02/08/2024] [Revised: 06/07/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Apples are among the most nutritionally valuable fruits and have a history of use in traditional Chinese medicine. Triterpenoids, the primary bioactive compounds found in apples, demonstrate significant antitumor activity. RESULTS Following enrichment and optimization, the total content of major triterpenoids in total triterpenoids from apple peels (ATT) reached 5.76 g kg-1. The growth of MDA-MB-231 xenograft tumors was significantly inhibited after treatment with ATT. Network pharmacology analysis conclusively identified a close association between the antitumor effect of ATT and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. Experimental validation using MDA-MB-231 cells and a xenograft nude mouse model confirmed that ATT suppressed tumor cell proliferation effectively by modulating the PI3K-Akt signaling pathway, which was consistent with the findings from network pharmacology. The total triterpenoids from apple peels also induced cell apoptosis by mediating the PI3K-Akt signaling pathway. CONCLUSION The total triterpenoids from apple peels can inhibit tumor cell proliferation and induce cell apoptosis effectively through the PI3K-Akt signaling pathway, suggesting that ATT holds promise as a prospective therapeutic agent for breast cancer treatment. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Wanyu Yan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, China
| | - Cong Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, China
| | - Yuanru Zheng
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, China
| | - Jingwen Xu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, China
| | - Yihai Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, China
| | - Xiangjiu He
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, China
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30
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Hassan D, Menges CW, Testa JR, Bellacosa A. AKT kinases as therapeutic targets. J Exp Clin Cancer Res 2024; 43:313. [PMID: 39614261 PMCID: PMC11606119 DOI: 10.1186/s13046-024-03207-4] [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: 07/24/2024] [Accepted: 10/03/2024] [Indexed: 12/01/2024] Open
Abstract
AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.
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Affiliation(s)
- Dalal Hassan
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, 901 Walnut St, Philadelphia, PA, 19107, USA
| | - Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
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Postu PA, Boiangiu RS, Mihasan M, Stache AB, Tiron A, Hritcu L. The Distinct Biological Effects of 6-Hydroxy-L-Nicotine in Representative Cancer Cell Lines. Molecules 2024; 29:5593. [PMID: 39683752 DOI: 10.3390/molecules29235593] [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: 10/21/2024] [Revised: 11/12/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
6-hydroxy-L-nicotine (6HLN) is a nicotine (NIC) derivative with proven therapeutic potential in neurodegenerative disorders. Here, the impact of 6HLN on cell growth, migratory behavior, and inflammatory status of three different cancer cell lines (A549, MCF7, and U87) and two normal cell lines (16HBE14o and MCF10A) was investigated. In silico analyses were conducted to evaluate the binding affinity of 6HLN to nicotinic receptors (nAChRs) containing α9 and α5 subunits. The obtained in silico data revealed that 6HLN might act on the cholinergic system. Interestingly, the in vitro data showed the compound has cancer-stimulatory effects in U87 glioblastoma cells and cancer-inhibitory effects in MCF7 breast cancer cells. In A549 lung cancer cells, no changes were detected upon 6HLN administration. More importantly, 6HLN appears not to be deleterious for normal cells, with the viability of 16HBE14o pulmonary cells and MCF10A mammary cells remaining unchanged.
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Affiliation(s)
- Paula Alexandra Postu
- Center for Fundamental Research and Experimental Development in Translation Medicine-TRANSCEND, Regional Institute of Oncology, 700483 Iasi, Romania
| | - Razvan Stefan Boiangiu
- Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania
| | - Marius Mihasan
- Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania
| | - Alexandru Bogdan Stache
- Center for Fundamental Research and Experimental Development in Translation Medicine-TRANSCEND, Regional Institute of Oncology, 700483 Iasi, Romania
| | - Adrian Tiron
- Center for Fundamental Research and Experimental Development in Translation Medicine-TRANSCEND, Regional Institute of Oncology, 700483 Iasi, Romania
| | - Lucian Hritcu
- Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, 700506 Iasi, Romania
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Li P, Zheng S, Leung HM, Liu LS, Chang TJH, Maryam A, Wang F, Chin YR, Lo PK. TNA-Mediated Antisense Strategy to Knockdown Akt Genes for Triple-Negative Breast Cancer Therapy. SMALL METHODS 2024; 8:e2400291. [PMID: 38779741 PMCID: PMC11579567 DOI: 10.1002/smtd.202400291] [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: 02/28/2024] [Revised: 05/11/2024] [Indexed: 05/25/2024]
Abstract
Triple-negative breast cancer (TNBC) remains a significant challenge in terms of treatment, with limited efficacy of chemotherapy due to side effects and acquired drug resistance. In this study, a threose nucleic acid (TNA)-mediated antisense approach is employed to target therapeutic Akt genes for TNBC therapy. Specifically, two new TNA strands (anti-Akt2 and anti-Akt3) are designed and synthesized that specifically target Akt2 and Akt3 mRNAs. These TNAs exhibit exceptional enzymatic resistance, high specificity, enhance binding affinity with their target RNA molecules, and improve cellular uptake efficiency compared to natural nucleic acids. In both 2D and 3D TNBC cell models, the TNAs effectively inhibit the expression of their target mRNA and protein, surpassing the effects of scrambled TNAs. Moreover, when administered to TNBC-bearing animals in combination with lipid nanoparticles, the targeted anti-Akt TNAs lead to reduced tumor sizes and decreased target protein expression compared to control groups. Silencing the corresponding Akt genes also promotes apoptotic responses in TNBC and suppresses tumor cell proliferation in vivo. This study introduces a novel approach to TNBC therapy utilizing TNA polymers as antisense materials. Compared to conventional miRNA- and siRNA-based treatments, the TNA system holds promise as a cost-effective and scalable platform for TNBC treatment, owing to its remarkable enzymatic resistance, inexpensive synthetic reagents, and simple production procedures. It is anticipated that this TNA-based polymeric system, which targets anti-apoptotic proteins involved in breast tumor development and progression, can represent a significant advancement in the clinical development of effective antisense materials for TNBC, a cancer type that lacks effective targeted therapy.
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Affiliation(s)
- Pan Li
- Department of Chemistry and State Key Laboratory of Marine PollutionCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
| | - Shixue Zheng
- Tung Biomedical Sciences CentreDepartment of Biomedical SciencesCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
| | - Hoi Man Leung
- Department of Chemistry and State Key Laboratory of Marine PollutionCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
| | - Ling Sum Liu
- Department of ChemistryMolecular Sciences Research HubImperial College LondonWhite City CampusWood LaneLondonW12 0BZU.K.
| | - Tristan Juin Han Chang
- Department of Chemistry and State Key Laboratory of Marine PollutionCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
| | - Alishba Maryam
- Tung Biomedical Sciences CentreDepartment of Biomedical SciencesCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
| | - Fei Wang
- The Tenth Affiliated HospitalSouthern Medical University (Dongguan People's Hospital)Dongguan523059P. R. China
| | - Y. Rebecca Chin
- Tung Biomedical Sciences CentreDepartment of Biomedical SciencesCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
| | - Pik Kwan Lo
- Department of Chemistry and State Key Laboratory of Marine PollutionCity University of Hong KongTat Chee AvenueKowloonHong Kong SARP. R. China
- Key Laboratory of Biochip TechnologyBiotechand Health CareShenzhen Research Institute of City University of Hong KongShenzhen518057P. R. China
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Zu GX, Sun KY, Liu XJ, Tang JQ, Huang HL, Han T. Banxia xiexin decoction prevents the development of gastric cancer. World J Clin Oncol 2024; 15:1293-1308. [DOI: 10.5306/wjco.v15.i10.1293] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/09/2024] [Accepted: 08/23/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND In China banxia xiexin decoction (BXD) has been used in treating gastric cancer (GC) for thousands of years and BXD has a good role in reversing GC histopathology, but its chemical composition and action mechanism are still unknown.
AIM To investigate the mechanism of action of BXD against GC based on transcriptomics, network pharmacology, in vivo and in vitro experiments.
METHODS The transplanted tumor model was prepared, and the nude mouse were pathologically examined after administration, and hematoxylin-eosin staining was performed. The active ingredients of BXD were quality controlled and identified using ultra-performance liquid chromatography tandem quadrupole electrostatic field orbitrap mass spectrometry (UPLC-Q-Orbitrap MS/MS), and traditional Chinese medicines systems pharmacology platform, drug bank and the Swiss target prediction platform to predict the relevant targets, the differentially expressed genes (DEGs) of GC were screened by RNA-seq sequencing, and the overlapping targets were analyzed to obtain the key targets and pathways. Cell Counting Kit-8, apoptosis assay, cell migration and Realtime fluorescence quantitative polymerase chain reaction were used for in vitro experiments.
RESULTS All dosing groups inhibited the growth of transplanted tumors in laboratory-bred strain nude, with the capecitabine group and the BXD medium-dose group being the best. A total of 29 compounds and 859 potential targets in BXD were identified by UPLC-Q-Orbitrap MS/MS and network pharmacology, RNA-seq sequencing found 4767 GC DEGs, which were combined with network pharmacology and analyzed 246 potential therapeutic targets were obtained and pathway results showed that BXD may against GC through the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKt) signaling pathway. In vitro cellular experiments confirmed that BXD-containing serum and LY294002 could inhibit the proliferation of GC cells, promote apoptosis, and inhibit the migration of GC cells by decreasing the expression of EGFR, PIK3CA, IL6, BCL2 and AKT1 in the PI3K-Akt pathway in MGC-803 expression.
CONCLUSION BXD has the effect of inhibiting tumor growth rate and delaying the development of GC. Its mechanism of action may be related to the regulation of PI3K-Akt signaling pathway.
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Affiliation(s)
- Guo-Xiu Zu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Ke-Yun Sun
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Xi-Jian Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Ji-Qin Tang
- School of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Hai-Liang Huang
- School of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
| | - Tao Han
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China
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Zhang W, Xiao Y, Zhou Q, Zhu X, Zhang Y, Xiang Q, Wu S, Song X, Zhao J, Yuan R, Xiao B, Li L. KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation. Biochem Genet 2024; 62:3709-3739. [PMID: 38198023 PMCID: PMC11427568 DOI: 10.1007/s10528-023-10615-2] [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: 09/25/2023] [Accepted: 11/29/2023] [Indexed: 01/11/2024]
Abstract
Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.
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Affiliation(s)
- Wenwu Zhang
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
- Department of Laboratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215008, China
| | - Yuhan Xiao
- School of Public Health, Dali University, Dali, 671000, China
| | - Quan Zhou
- Department of Laboratory Medicine, General Hospital of Southern Theater Command of People's Liberation Army (PLA), Guangzhou, 510010, China
| | - Xin Zhu
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Yanxia Zhang
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Qin Xiang
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Shunhong Wu
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Xiaoyu Song
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Junxiu Zhao
- School of Public Health, Dali University, Dali, 671000, China
| | - Ruanfei Yuan
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Bin Xiao
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.
| | - Linhai Li
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.
- Department of Laboratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215008, China.
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Wu Z, Xiang H, Wang X, Zhang R, Guo Y, Qu L, Zhou J, Xiao Y. Integrating network pharmacology, molecular docking and experimental verification to explore the therapeutic effect and potential mechanism of nomilin against triple-negative breast cancer. Mol Med 2024; 30:166. [PMID: 39342122 PMCID: PMC11439318 DOI: 10.1186/s10020-024-00928-2] [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: 06/13/2024] [Accepted: 09/06/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND Nomilin is a limonoid compound known for its multiple biological activities, but its role in triple negative breast cancer (TNBC) remains unclear. This study aims to uncover the potential therapeutic effect of nomilin on TNBC and elucidate the specific mechanism of its action. METHODS We employed weighted gene co-expression network analysis (WGCNA), differential expression analysis, and the GeneCards database to identify potential targets for TNBC. Simultaneously, we utilized the Swiss Target Prediction, ChEMBL, and STITCH databases to identify potential targets of nomilin. The core targets and mechanisms of nomilin against TNBC were predicted through protein-protein interaction (PPI) network analysis, molecular docking, and enrichment analysis. The results of the network pharmacology were corroborated by conducting experiments. RESULTS A total of 17,204 TNBC targets were screened, and 301 potential targets of nomilin were identified. Through the PPI network, eight core targets of nomilin against TNBC were pinpointed, namely BCL2, Caspase3, CyclinD1, EGFR, HSP90AA1, KRAS, PARP1, and TNF. Molecular docking, molecular dynamics simulation and proteome microarray revealed that nomilin exhibits strong binding activity to these core proteins. Enrichment analysis results indicated that the anti-TNBC effect of nomilin is associated with PI3K/Akt pathway. In vitro and in vivo experiments have demonstrated that nomilin inhibits TNBC cell proliferation and migration while promoting cell apoptosis through the PI3K/Akt pathway. CONCLUSION For the first time, the research effectively discovered the objectives and mechanisms of nomilin in combating TNBC using network pharmacology, molecular docking, molecular dynamics simulation, proteome microarray and experimental confirmation, presenting a hopeful approach for treating TNBC.
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Affiliation(s)
- Zhixuan Wu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China
| | - Haoyi Xiang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310016, China
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang Province, 310016, China
| | - Xiaowu Wang
- Department of Burns and Skin Repair Surgery, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, 325200, China
| | - Rongrong Zhang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China
| | - Yangyang Guo
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China
| | - Liangchen Qu
- Emergency Department, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, 318000, China.
| | - Jingyao Zhou
- Pharmacy Department, Taizhou Central Hospital, Taizhou, Zhejiang Province, 318000, China.
| | - Yanyi Xiao
- The Dingli Clinical College of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, China.
- Department of Thyroid and Breast Surgery, Wenzhou Central Hospital, The Second Affiliated Hospital of Shanghai University, Wenzhou, Zhejiang Province, 325000, China.
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Tosi G, Paoli A, Zuccolotto G, Turco E, Simonato M, Tosoni D, Tucci F, Lugato P, Giomo M, Elvassore N, Rosato A, Cogo P, Pece S, Santoro MM. Cancer cell stiffening via CoQ 10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer. Nat Commun 2024; 15:8214. [PMID: 39294175 PMCID: PMC11410950 DOI: 10.1038/s41467-024-52523-y] [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: 04/19/2023] [Accepted: 09/11/2024] [Indexed: 09/20/2024] Open
Abstract
CoQ10 (Coenzyme Q10) is an essential fat-soluble metabolite that plays a key role in cellular metabolism. A less-known function of CoQ10 is whether it may act as a plasma membrane-stabilizing agent and whether this property can affect cancer development and progression. Here, we show that CoQ10 and its biosynthetic enzyme UBIAD1 play a critical role in plasmamembrane mechanical properties that are of interest for breast cancer (BC) progression and treatment. CoQ10 and UBIAD1 increase membrane fluidity leading to increased cell stiffness in BC. Furthermore, CoQ10 and UBIAD1 states impair ECM (extracellular matrix)-mediated oncogenic signaling and reduce ferroptosis resistance in BC settings. Analyses on human patients and mouse models reveal that UBIAD1 loss is associated with BC development and progression and UBIAD1 expression in BC limits CTCs (circulating tumor cells) survival and lung metastasis formation. Overall, this study reveals that CoQ10 and UBIAD1 can be further investigated to develop therapeutic interventions to treat BC patients with poor prognosis.
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Affiliation(s)
- Giovanni Tosi
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Alessandro Paoli
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Gaia Zuccolotto
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Emilia Turco
- Molecular Biotechnology Center, University of Turin, Torino, Italy
| | - Manuela Simonato
- Pediatric Research Institute "Città della Speranza", Padova, Italy
| | | | | | - Pietro Lugato
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Monica Giomo
- Department of Industrial Engineering, University of Padova, Padova, Italy
| | - Nicola Elvassore
- Department of Industrial Engineering, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Antonio Rosato
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Paola Cogo
- Pediatric Research Institute "Città della Speranza", Padova, Italy
- Division of Pediatrics, Department of Medicine, Udine University, Udine, Italy
| | - Salvatore Pece
- IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milano, Italy
| | - Massimo M Santoro
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy.
- Veneto Institute of Molecular Medicine, Padova, Italy.
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Durrani IA, John P, Bhatti A, Khan JS. Network medicine based approach for identifying the type 2 diabetes, osteoarthritis and triple negative breast cancer interactome: Finding the hub of hub genes. Heliyon 2024; 10:e36650. [PMID: 39281650 PMCID: PMC11401126 DOI: 10.1016/j.heliyon.2024.e36650] [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: 08/10/2024] [Accepted: 08/20/2024] [Indexed: 09/18/2024] Open
Abstract
The increasing prevalence of multi-morbidities, particularly the incidence of breast cancer in diabetic/osteoarthritic patients emphasize on the need for exploring the underlying molecular mechanisms resulting in carcinogenesis. To address this, present study employed a systems biology approach to identify switch genes pivotal to the crosstalk between diseased states resulting in multi-morbid conditions. Hub genes previously reported for type 2 diabetes mellitus (T2DM), osteoarthritis (OA), and triple negative breast cancer (TNBC), were extracted from published literature and fed into an integrated bioinformatics analyses pipeline. Thirty-one hub genes common to all three diseases were identified. Functional enrichment analyses showed these were mainly enriched for immune and metabolism associated terms including advanced glycation end products (AGE) pathways, cancer pathways, particularly breast neoplasm, immune system signalling and adipose tissue. The T2DM-OA-TNBC interactome was subjected to protein-protein interaction network analyses to identify meta hub/clustered genes. These were prioritized and wired into a three disease signalling map presenting the enriched molecular crosstalk on T2DM-OA-TNBC axes to gain insight into the molecular mechanisms underlying disease-disease interactions. Deciphering the molecular bases for the intertwined metabolic and immune states may potentiate the discovery of biomarkers critical for identifying and targeting the immuno-metabolic origin of disease.
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Affiliation(s)
- Ilhaam Ayaz Durrani
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, 44000, Pakistan
| | - Peter John
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, 44000, Pakistan
| | - Attya Bhatti
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, 44000, Pakistan
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Alhamdi HW, Alfaifi MY, Shati AA, Elbehairi SEI, Er-Rajy M, Elshaarawy RFM, Hassan YA, Zakrya R. New multifunctional hybrids as modulators of apoptosis markers and topoisomerase II in breast cancer therapy: synthesis, characterization, and in vitro and in silico studies. RSC Adv 2024; 14:28555-28568. [PMID: 39247509 PMCID: PMC11378026 DOI: 10.1039/d4ra04219k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/22/2024] [Indexed: 09/10/2024] Open
Abstract
Recently, molecular hybrids of two or more active pharmacophores have shown promise for designing and synthesizing anticancer drugs. Herein, a new multifunctional hybrid (PAHMQ), combining azobenzene and quinoline pharmacophores, and its M(ii) complexes (MPAHMQ) have been successfully developed and structurally characterized. The MTT assay revealed CuBHTP as the most efficient and safe breast cancer treatment, with an IC50 of 11.18 ± 0.39 μg mL-1 and a high selectivity index (SI) of 5.63 for cancer MCF-7 cells over healthy MCF10A cells. Moreover, the CuPAHMQ-treated MCF-7 cells experience a dramatic impact with regard to key apoptotic markers, including an increase in P53 and Bax expression, with a decrease in Bcl-2 expression levels compared to the untreated MCF-7 cells. Additionally, CuPAHMQ effectively halted the growth and division of MCF-7 cells by inducing cell cycle arrest in the crucial G1 and S phases, ultimately inhibiting both Topo II activity and cell proliferation. Molecular docking investigations validated the CuPAHMQ complex's groove binding and topoisomerase II binding, establishing it as a potent anticancer drug.
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Affiliation(s)
- Heba W Alhamdi
- College of Sciences, Biology Department, King Khalid University Abha 61413 Saudi Arabia
| | - Mohammad Y Alfaifi
- King Khalid University, Faculty of Science, Biology Department Abha 9004 Saudi Arabia
- Tissue Culture and Cancer Biology Research Laboratory, King Khalid University Abha 9004 Saudi Arabia
| | - Ali A Shati
- King Khalid University, Faculty of Science, Biology Department Abha 9004 Saudi Arabia
- Tissue Culture and Cancer Biology Research Laboratory, King Khalid University Abha 9004 Saudi Arabia
| | - Serag Eldin I Elbehairi
- King Khalid University, Faculty of Science, Biology Department Abha 9004 Saudi Arabia
- Tissue Culture and Cancer Biology Research Laboratory, King Khalid University Abha 9004 Saudi Arabia
- Cell Culture Lab, Egyptian Organization for Biological Products and Vaccines (VACSERA Holding Company) 51 Wezaret El-Zeraa St., Agouza Giza Egypt
| | - Mohammed Er-Rajy
- LIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University Fez Morocco
| | - Reda F M Elshaarawy
- Department of Chemistry, Faculty of Science, Suez University 43533 Suez Egypt
| | - Yasser A Hassan
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology Gamasa Egypt
| | - Rozan Zakrya
- Chemistry Department, Faculty of Science, Port-Said University Port-Said Egypt
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Ji T, Ye L, Xi E, Liu Y, Wang X, Wang S. Sinensetin Inhibits Angiogenesis in Lung Adenocarcinoma via the miR-374c-5p/VEGF-A/VEGFR-2/AKT Axis. Cell Biochem Biophys 2024; 82:2413-2425. [PMID: 39030333 DOI: 10.1007/s12013-024-01352-3] [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] [Accepted: 06/04/2024] [Indexed: 07/21/2024]
Abstract
Sinensetin is a product isolated from Orthosiphon aristatus, and its antitumor activities have been well established. This study focused on the role and mechanism of sinensetin in lung adenocarcinoma (LUAD). LUAD cells were treated with various concentrations of sinensetin. The proliferation, migration, invasion, and angiogenesis of LUAD cells were detected using colony formation, transwell, and tube formation assays, respectively. The protein levels of VEGF-A, VEGFR-2, and phosphorylated AKT (ser473) were measured by western blotting. The targeted relationship between VEGF-A and miR-374c-5p was verified by luciferase reporter assay. BALB/c nude mice inoculated with A549 cells were treated with sinensetin (40 mg/kg/day) by gavage for 21 days to investigate the effect of sinensetin on tumor growth and angiogenesis in vivo. We found that sinensetin reduced proliferation, migration, invasion, angiogenesis, and cancer stem characteristics of LUAD cells. Sinensetin also suppressed LUAD tumor growth and angiogenesis in vivo. Sinensetin downregulated VEGF-A expression in LUAD cells by enhancing miR-374c-5p expression. MiR-374c-5p inhibited the VEGF-A/VEGFR-2/AKT pathway in LUAD cells. The antitumor effect of sinensetin was reversed by overexpression of VEGF-A or inhibition of miR-374c-5p. Overall, sinensetin upregulates miR-374c-5p to inhibit the VEGF-A/VEGFR-2/AKT pathway, thereby exerting antitumor effect on LUAD.
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Affiliation(s)
- Tao Ji
- Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan, 430070, China
| | - Lin Ye
- Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan, 430070, China
| | - Erping Xi
- Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan, 430070, China
| | - Ying Liu
- Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan, 430070, China
| | - Xiumei Wang
- Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan, 430070, China
| | - Sha Wang
- Department of Dermatology, General Hospital of Central Theater Command, Wuhan, 430070, China.
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Suwannalert P, Panpinyaporn P, Wantanachaisaeng P, Teeppaibul T, Worawichitchaikun T, Koomsang T, Naktubtim C, Payuhakrit W. 17-AAG Induces Endoplasmic Reticulum Stress-mediated Apoptosis in Breast Cancer Cells, Possibly Through PERK/eIF2α Up-regulation. In Vivo 2024; 38:2228-2238. [PMID: 39187325 PMCID: PMC11363749 DOI: 10.21873/invivo.13687] [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: 04/20/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND/AIM Breast cancer is the most predominant type of cancer affecting women worldwide and the current therapeutic treatment for breast cancer patients is not adequately effective. This study aimed to investigate the mechanism of 17-AAG, a heat shock protein (HSP90) inhibitor, as a treatment for inducing breast cancer cell apoptosis. MATERIALS AND METHODS The pharmacology network was employed to examine the correlation of 17-AAG with the gene expression profiles of breast cancer, obtained by Gene Expression Profiling Interactive Analysis (GEPIA). MTT and flow cytometry were utilized to investigate cell proliferation and cell apoptosis, respectively. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay and western blot analysis were employed to examine the correlation between cellular oxidant levels and protein expression. Immunofluorescence staining was utilized to confirm the protein localization and assess DNA damage. RESULTS The pharmacological network analysis revealed that HSP90 serves as the common target connecting 17-AAG and breast cancer genes. Treatment with 17-AAG significantly increased cell apoptosis. Moreover, the treatment resulted in up-regulation of cellular oxidant levels and PERK/eIF2α expression. In line with these, protein localization after treatment revealed an increase in DNA damage, correlating with higher ER stress levels. Furthermore, GEPIA demonstrated that PERK and eIF2α expression were significantly higher in breast invasive carcinoma compared to other tumor types. CONCLUSION HSP90 emerges as a potential target for inducing apoptosis in breast cancer cells by disrupting protein homeostasis in the endoplasmic reticulum, possibly through PERK/eIF2α up-regulation. 17-AAG, an HSP90 inhibitor, may therefore potentially hold an alternative therapeutic strategy for breast cancer treatment.
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Affiliation(s)
- Prasit Suwannalert
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | | | - Teerapat Teeppaibul
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | - Thidarat Koomsang
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Chonnapat Naktubtim
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Witchuda Payuhakrit
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
- Pathobiology Information and Learning Center, Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand
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Long T, Tan M. To investigate the role and potential mechanism of has_circ_RBMS3 in bone metastasis of breast cancer based on bioinformatics. Cell Biochem Biophys 2024; 82:2227-2236. [PMID: 38822975 DOI: 10.1007/s12013-024-01332-7] [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] [Accepted: 05/21/2024] [Indexed: 06/03/2024]
Abstract
Circular RNAs (circRNAs) play a crucial regulatory role in malignant tumor metastasis. This study focused on the role of bone metastasis-related circRBMS3 in breast cancer. Two circRNA microarray datasets were obtained from the GEO database and overlapped bone metastasis-related circRNAs in breast cancer. CircRBMS3 expression was validated in bone metastasis tissues by RT-qPCR. Cellular CCK-8 assay and Transwell assays were performed to measure the effect of circRBMS3 in breast cancer cells. Bioinformatic analyses were performed to identify the binding miRNAs of circRBMS3 and downstream mRNAs. Online database STRING and Cytoscape software were used to analyze PPI interaction and conduct the ceRNA network. GEO database analysis showed that circRBMS3 was one of the upregulated circRNAs among all the metastatic cells. CircRBMS3 was increased in bone metastasis breast cancer tissues compared to non-bone metastasis tissues and associated with poor 3-year overall survival. CircRBMS3 knockdown repressed breast cancer cell proliferation, migration, and invasion, as well as bone resorption gene and osteoclast phenotype gene expression. CircRBMS3 was found to bind withmiR-654-3p. Subsequently, downstream mRNAs were predicted, and the circRBMS3 miR-654-3p-mRNA network was established. In conclusion, circRBMS3 expression was upregulated in bone metastasis breast cancer and might be a potential prognostic marker for patients. Silencing circRBMS3 restrained breast cancer cell proliferation, migration, and invasion, as well as associated with bone metastasis. The circRBMS3-miR-654-3p-mRNAs network elucidated potential mechanisms underlying bone metastasis in breast cancer.
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Affiliation(s)
- Ting Long
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, China
- West China School of Nursing, Sichuan University, Chengdu, Sichuan, 610044, China
| | - Mingying Tan
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, Sichuan, 610044, China.
- West China School of Nursing, Sichuan University, Chengdu, Sichuan, 610044, China.
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Nandwa JO, Mehmood A, Mahjabeen I, Raheem KY, Hamadou M, Raimi MZ, Kayani MA. miR-4716-3p and the target AKT2 Gene/rs2304186 SNP are associated with blood cancer pathogenesis in Pakistani population. Noncoding RNA Res 2024; 9:695-703. [PMID: 38577021 PMCID: PMC10990746 DOI: 10.1016/j.ncrna.2024.03.005] [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: 01/25/2024] [Revised: 02/28/2024] [Accepted: 03/13/2024] [Indexed: 04/06/2024] Open
Abstract
AKT2 is crucial for cancer cells' invasion, metastasis, and survival. It is a possible downstream gene target of cancer glycolysis-related microRNAs. The study investigated the role of miRNA-4716-3p, rs2304186, and the AKT2 gene in blood cancer pathogenesis. RT-qPCR was used to analyze AKT2 gene mRNA and miRNA-4716-3p expression in 200 blood cancer samples and 200 healthy controls. Furthermore, Tetra-ARMS PCR was used to examine the rs2304186 AKT2 SNP in 300 patients and 290 control samples. miRNA-4716-3p was shown to be significantly downregulated (p = 0.0294), whereas mRNA expression of the AKT2 gene was found to be significantly upregulated (p = 0.0034) in blood cancer patients compared to healthy individuals. miRNA-4716-3p downregulation (p = 0.0466) was more pronounced, while AKT2 upregulation was non-significant (p = 0.1661) in untreated patients compared to chemotherapy-treated patients. Blood cancer risk was significantly associated with the rs2304186 GT genotype (p = 0.0432), TT genotype (p = 0.0502), and mutant allele (T) frequency (p = 0.0008). Polymorphism rs2304186 was associated with an increased risk of blood cancer in dominant (p = 0.0011), recessive (p = 0.0502), and additive (p = 0.0008) genetic models. The results suggested that the rs2304186 and the deregulated expression of miRNA-4716-3p and AKT2 gene at the mRNA level may significantly increase the incidence of blood cancer, particularly in the Pakistani population. Therefore, these may function as suitable biomarkers for blood cancer diagnosis and prognosis. Additional, larger-scale investigations may be required to affirm these results.
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Affiliation(s)
- Jairus Olumasai Nandwa
- Department of Biosciences, COMSATS University Islamabad, Pakistan
- Department of Public Needs Research, Integrated Cancer Research Foundation of Kenya, Kenya
- Department of Genetics, Hebrew University of Jerusalem, Israel
| | - Azhar Mehmood
- Department of Biosciences, COMSATS University Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Department of Biosciences, COMSATS University Islamabad, Pakistan
| | | | - Mamoudou Hamadou
- Department of Biological Sciences, Faculty of Science, University of Maroua, Cameroon
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Notomi R, Sasaki S, Taniguchi Y. Novel strategy for activating gene expression through triplex DNA formation targeting epigenetically suppressed genes. RSC Chem Biol 2024; 5:884-890. [PMID: 39211471 PMCID: PMC11353075 DOI: 10.1039/d4cb00134f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Triplex DNA formation is a useful genomic targeting tool that is expected to have a wide range of applications, including the antigene method; however, there are fundamental limitations in its forming sequence. We recently extended the triplex DNA-forming sequence to methylated DNA sequences containing 5mCG base pairs by developing guanidino-dN, which is capable of recognizing a 5mCG base pair with high affinity. We herein investigated the effect of triplex DNA formation using TFOs with guanidino-dN on methylated DNA sequences at the promoter of the RASSF1A gene, whose expression is epigenetically suppressed by DNA methylation in MCF-7 cells, on gene expression. Interestingly, triplex DNA formation increased the expression of the RASSF1A gene at the transcript and protein levels. Furthermore, RASSF1A-activated MCF-7 cells exhibited cell growth suppressing activity. Changes in the expression of various genes associated with the promotion of apoptosis and breast cancer survival accompanied the activation of RASSF1A in cells exhibited antiproliferative activity. These results suggest the potential of increases in gene expression through triplex DNA formation as a new genomic targeting tool.
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Affiliation(s)
- Ryotaro Notomi
- Graduate School of Pharmaceutical Sciences, Kyushu University 3-1-1 Maidashi Higashi-ku Fukuoka 812-8582 Japan
| | - Shigeki Sasaki
- Graduate School of Pharmaceutical Sciences, Nagasaki International University 22825-7 Huis Ten Bosch Machi Sasebo city Nagasaki 859-3298 Japan
| | - Yosuke Taniguchi
- Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 1-1-1 Tsushima-naka Kita-ku Okayama 700-8530 Japan
- Graduate School of Pharmaceutical Sciences, Kyushu University 3-1-1 Maidashi Higashi-ku Fukuoka 812-8582 Japan
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Ray P, Sarker DK, Uddin SJ. Bioinformatics and computational studies of chabamide F and chabamide G for breast cancer and their probable mechanisms of action. Sci Rep 2024; 14:19893. [PMID: 39191884 DOI: 10.1038/s41598-024-70854-0] [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: 06/14/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024] Open
Abstract
Globally, the prevalence of breast cancer (BC) is increasing at an alarming level, despite early detection and technological improvements. Alkaloids are diverse chemical groups, and many within this class have been reported as potential anticancer compounds. Chabamide F (F) and chabamide G (G) are two dimeric amide alkaloids found in a traditional medicinal plant, Piper chaba, and possess significant cytotoxic effects. However, their scientific rationalization in BC remains unknown. Here, we aimed to investigate their potential and molecular mechanisms for BC through in silico approaches. From network pharmacology, we identified 64 BC-related genes as targets. GO and KEGG studies showed that they were involved in various biological processes and mostly expressed in BC-related pathways such as RAS, PI3K-AKT, estrogen, MAPK, and FoxO pathways. However, PPI analysis revealed SRC and AKT1 as hub genes, which play key roles in BC tumorigenesis and metastasis. Molecular docking revealed the strong binding affinity of F (- 10.7 kcal/mol) and G (- 9.4 and - 11.7 kcal/mol) for SRC and AKT1, respectively, as well as the acquisition of vital residues to inhibit them. Their long-term stability was evaluated using 200 ns molecular dynamics simulation. The RMSD, RMSF, Rg, and SASA analyses showed that the G-SRC and G-AKT1 complexes were excellently stable compared to the control, dasatinib, and capivasertib, respectively. Additionally, the PCA and DCCM analyses revealed a significant reduction in the residual correlation and motions. By contrast, the stability of the F-SRC complex was greater than that of the control, whereas it was moderately stable in complex with AKT1. The MMPBSA analysis demonstrated higher binding energies for both compounds than the controls. In particular, the binding energy of G for SRC and AKT1 was - 120.671 ± 16.997 and - 130.437 ± 19.111 kJ/mol, respectively, which was approximately twice as high as the control molecules. Van der Waal and polar solvation energies significantly contributed to this energy. Furthermore, both of them exhibited significant interactions with the binding site residues of both proteins. In summary, this study indicates that these two molecules could be a potential ATP-competitive inhibitor of SRC and an allosteric inhibitor of AKT1.
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Affiliation(s)
- Pallobi Ray
- Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9208, Bangladesh
| | - Dipto Kumer Sarker
- Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9208, Bangladesh
- Department of Pharmacy, Atish Dipankar University of Science & Technology, Dhaka, 1230, Bangladesh
| | - Shaikh Jamal Uddin
- Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9208, Bangladesh.
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Li H, Wen X, Ren Y, Fan Z, Zhang J, He G, Fu L. Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions. Mol Cancer 2024; 23:164. [PMID: 39127670 DOI: 10.1186/s12943-024-02072-1] [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: 06/15/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family.
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Affiliation(s)
- Hongyao Li
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
- Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan University, Chengdu, 610041, China
| | - Xiang Wen
- Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan University, Chengdu, 610041, China
| | - Yueting Ren
- Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan University, Chengdu, 610041, China
- Department of Brain Science, Faculty of Medicine, Imperial College, London, SW72AZ, UK
| | - Zhichao Fan
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
- Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan University, Chengdu, 610041, China
| | - Jin Zhang
- School of Pharmaceutical Sciences of Medical School, Shenzhen University, Shenzhen, 518000, China.
| | - Gu He
- Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan University, Chengdu, 610041, China.
| | - Leilei Fu
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China.
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
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Kim B, Chun H, Lee J, Park M, Kwak Y, Kim JM, Kim SG, Ryu JK, Choi J, Cho S. Predictive biomarkers for metachronous gastric cancer development after endoscopic resection of early gastric cancer. Cancer Med 2024; 13:e70104. [PMID: 39171503 PMCID: PMC11339598 DOI: 10.1002/cam4.70104] [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: 02/08/2024] [Revised: 07/21/2024] [Accepted: 08/04/2024] [Indexed: 08/23/2024] Open
Abstract
OBJECTIVES We aimed to identify predictive markers for metachronous gastric cancer (MGC) in early gastric cancer (EGC) patients curatively treated with endoscopic submucosal dissection (ESD). MATERIALS AND METHODS From EGC patients who underwent ESD, bulk RNA sequencing was performed on non-cancerous gastric mucosa samples at the time of initial EGC diagnosis. This included 23 patients who developed MGC, and 23 control patients without additional gastric neoplasms for over 3 years (1:1 matched by age, sex, and Helicobacter pylori infection state). Candidate differentially-expressed genes were identified, from which biomarkers were selected using real-time quantitative polymerase chain reaction and cell viability assays using gastric cell lines. An independent validation cohort of 55 MGC patients and 125 controls was used for marker validation. We also examined the severity of gastric intestinal metaplasia, a known premalignant condition, at initial diagnosis. RESULTS From the discovery cohort, 86 candidate genes were identified of which KDF1 and CDK1 were selected as markers for MGC, which were confirmed in the validation cohort. CERB5 and AKT2 isoform were identified as markers related to intestinal metaplasia and were also highly expressed in MGC patients compared to controls (p < 0.01). Combining these markers with clinical data (age, sex, H. pylori and severity of intestinal metaplasia) yielded an area under the curve (AUC) of 0.91 (95% CI, 0.85-0.97) for MGC prediction. CONCLUSION Assessing biomarkers in non-cancerous gastric mucosa may be a useful method for predicting MGC in EGC patients and identifying patients with a higher risk of developing MGC, who can benefit from rigorous surveillance.
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Affiliation(s)
- Bokyung Kim
- Department of Internal Medicine and Liver Research InstituteSeoul National University Hospital, Seoul National University College of MedicineSeoulKorea
| | - Harim Chun
- Department of Biomedical SciencesKorea University College of MedicineSeoulKorea
| | - Jongwon Lee
- Department of Biomedical SciencesKorea University College of MedicineSeoulKorea
| | - Miree Park
- Department of Internal Medicine and Liver Research InstituteSeoul National University Hospital, Seoul National University College of MedicineSeoulKorea
| | - Yoonjin Kwak
- Department of PathologySeoul National University HospitalSeoulKorea
| | - Jung Mogg Kim
- Department of MicrobiologyHanyang University College of MedicineSeoulKorea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research InstituteSeoul National University Hospital, Seoul National University College of MedicineSeoulKorea
| | - Ji Kon Ryu
- Department of Internal Medicine and Liver Research InstituteSeoul National University Hospital, Seoul National University College of MedicineSeoulKorea
| | - Jungmin Choi
- Department of Biomedical SciencesKorea University College of MedicineSeoulKorea
| | - Soo‐Jeong Cho
- Department of Internal Medicine and Liver Research InstituteSeoul National University Hospital, Seoul National University College of MedicineSeoulKorea
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Simionato D, Collesei A, Miglietta F, Vandin F. ALLSTAR: Inference of ReliAble CausaL RuLes between Somatic MuTAtions and CanceR Phenotypes. Bioinformatics 2024; 40:btae449. [PMID: 39037955 PMCID: PMC11520414 DOI: 10.1093/bioinformatics/btae449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 04/11/2024] [Accepted: 07/19/2024] [Indexed: 07/24/2024] Open
Abstract
MOTIVATION Recent advances in DNA sequencing technologies have allowed the detailed characterization of genomes in large cohorts of tumors, highlighting their extreme heterogeneity, with no two tumors sharing the same complement of somatic mutations. Such heterogeneity hinders our ability to identify somatic mutations important for the disease, including mutations that determine clinically relevant phenotypes (e.g., cancer subtypes). Several tools have been developed to identify somatic mutations related to cancer phenotypes. However, such tools identify correlations between somatic mutations and cancer phenotypes, with no guarantee of highlighting causal relations. RESULTS We describe ALLSTAR, a novel tool to infer reliable causal relations between somatic mutations and cancer phenotypes. ALLSTAR identifies reliable causal rules highlighting combinations of somatic mutations with the highest impact in terms of average effect on the phenotype. While we prove that the underlying computational problem is NP-hard, we develop a branch-and-bound approach that employs protein-protein interaction networks and novel bounds for pruning the search space, while properly correcting for multiple hypothesis testing. Our extensive experimental evaluation on synthetic data shows that our tool is able to identify reliable causal relations in large cancer cohorts. Moreover, the reliable causal rules identified by our tool in cancer data show that our approach identifies several somatic mutations known to be relevant for cancer phenotypes as well as novel biologically meaningful relations. AVAILABILITY AND IMPLEMENTATION Code, data, and scripts to reproduce the experiments available at https://github.com/VandinLab/ALLSTAR. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Dario Simionato
- Department of Information Engineering, University of Padua, Via Giovanni Gradenigo 6b, Padua, 35131, Italy
| | - Antonio Collesei
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, 35128, Italy
- Bioinformatics, Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, 35128, Italy
| | - Federica Miglietta
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, 35128, Italy
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, 35128, Italy
| | - Fabio Vandin
- Department of Information Engineering, University of Padua, Via Giovanni Gradenigo 6b, Padua, 35131, Italy
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Jiang Q, Xiao J, Hsieh YC, Kumar NL, Han L, Zou Y, Li H. The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma. Biomedicines 2024; 12:1610. [PMID: 39062182 PMCID: PMC11274428 DOI: 10.3390/biomedicines12071610] [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: 06/14/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Dysfunction in components of this pathway, such as hyperactivity of PI3K, loss of PTEN function, and gain-of-function mutations in AKT, are well-known drivers of treatment resistance and disease progression in cancer. In this review, we discuss the major mutations and dysregulations in the PAM signaling pathway in HNSCC. We highlight the results of clinical trials involving inhibitors targeting the PAM signaling pathway as a strategy for treating HNSCC. Additionally, we examine the primary mechanisms of resistance to drugs targeting the PAM pathway and potential therapeutic strategies.
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Affiliation(s)
- Qian Jiang
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210093, China; (Q.J.)
- International Dentist Pathway, University of California, San Francisco, CA 94158, USA
| | - Jingyi Xiao
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210093, China; (Q.J.)
| | - Yao-Ching Hsieh
- International Dentist Pathway, University of California, San Francisco, CA 94158, USA
| | - Neha Love Kumar
- International Dentist Pathway, University of California, San Francisco, CA 94158, USA
| | - Lei Han
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210093, China; (Q.J.)
| | - Yuntao Zou
- Division of Hospital Medicine, University of California, San Francisco, CA 94158, USA
| | - Huang Li
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing 210093, China; (Q.J.)
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Sutherland L, Lang J, Gonzalez-Juarbe N, Pickett BE. Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer. Curr Issues Mol Biol 2024; 46:7114-7133. [PMID: 39057065 PMCID: PMC11275280 DOI: 10.3390/cimb46070424] [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: 06/09/2024] [Revised: 06/26/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two significant differentially expressed genes (DEGs) between these patient cohorts, with "PLK1 signaling events" being the most significant signaling pathway. We also identified PRDX4 and E2F8 gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients.
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Affiliation(s)
- Lincoln Sutherland
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
| | - Jacob Lang
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
| | - Norberto Gonzalez-Juarbe
- J. Craig Venter Institute, Rockville, MD 20850, USA;
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Brett E. Pickett
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
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Park S, Choi J, Ko N, Mondal S, Pal U, Lee BI, Oh J. Beta cyclodextrin conjugated AuFe 3O 4 Janus nanoparticles with enhanced chemo-photothermal therapy performance. Acta Biomater 2024; 182:213-227. [PMID: 38734286 DOI: 10.1016/j.actbio.2024.05.008] [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: 01/28/2024] [Revised: 04/16/2024] [Accepted: 05/05/2024] [Indexed: 05/13/2024]
Abstract
The strategic integration of multi-functionalities within a singular nanoplatform has received growing attention for enhancing treatment efficacy, particularly in chemo-photothermal therapy. This study introduces a comprehensive concept of Janus nanoparticles (JNPs) composed of Au and Fe3O4 nanostructures intricately bonded with β-cyclodextrins (β-CD) to encapsulate 5-Fluorouracil (5-FU) and Ibuprofen (IBU). This strategic structure is engineered to exploit the synergistic effects of chemo-photothermal therapy, underscored by their exceptional biocompatibility and photothermal conversion efficiency (∼32.88 %). Furthermore, these β-CD-conjugated JNPs enhance photodynamic therapy by generating singlet oxygen (1O2) species, offering a multi-modality approach to cancer eradication. Computer simulation results were in good agreement with in vitro and in vivo assays. Through these studies, we were able to prove the improved tumor ablation ability of the drug-loaded β-CD-conjugated JNPs, without inducing adverse effects in tumor-bearing nude mice. The findings underscore a formidable tumor ablation potency of β-CD-conjugated Au-Fe3O4 JNPs, heralding a new era in achieving nuanced, highly effective, and side-effect-free cancer treatment modalities. STATEMENT OF SIGNIFICANCE: The emergence of multifunctional nanoparticles marks a pivotal stride in cancer therapy research. This investigation unveils Janus nanoparticles (JNPs) amalgamating gold (Au), iron oxide (Fe3O4), and β-cyclodextrins (β-CD), encapsulating 5-Fluorouracil (5-FU) and Ibuprofen (IBU) for synergistic chemo-photothermal therapy. Demonstrating both biocompatibility and potent photothermal properties (∼32.88 %), these JNPs present a promising avenue for cancer treatment. Noteworthy is their heightened photodynamic efficiency and remarkable tumor ablation capabilities observed in vitro and in vivo, devoid of adverse effects. Furthermore, computational simulations validate their interactions with cancer cells, bolstering their utility as an emerging therapeutic modality. This endeavor pioneers a secure and efficacious strategy for cancer therapy, underscoring the significance of β-CD-conjugated Au-Fe3O4 JNPs as innovative nanoplatforms with profound implications for the advancement of cancer therapy.
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Affiliation(s)
- Sumin Park
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Jaeyeop Choi
- Smart Gym-Based Translational Research Center for Active Senior's Healthcare, Pukyong National University, Busan 48513, Republic of Korea
| | - Namsuk Ko
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Republic of Korea
| | - Sudip Mondal
- Digital Healthcare Research Center, Pukyong National University, Busan 48513, Republic of Korea
| | - Umapada Pal
- Institute of Physics, Autonomous University of Puebla, Puebla 72570, Mexico
| | - Byeong-Il Lee
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Republic of Korea; Smart Gym-Based Translational Research Center for Active Senior's Healthcare, Pukyong National University, Busan 48513, Republic of Korea; Digital Healthcare Research Center, Pukyong National University, Busan 48513, Republic of Korea; Department of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea.
| | - Junghwan Oh
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan 48513, Republic of Korea; Smart Gym-Based Translational Research Center for Active Senior's Healthcare, Pukyong National University, Busan 48513, Republic of Korea; Digital Healthcare Research Center, Pukyong National University, Busan 48513, Republic of Korea; Department of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea; Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea; Ohlabs Corp., Busan 48513, Republic of Korea.
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