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Bayindir-Bilgic M, Duman E, Turgut D, Kadikoylu AN, Ekimci-Gurcan N, Ozbey U, Kuskucu A, Bayrak OF. Investigation of the synergistic effect of metformin and FX11 on PANC-1 cell lines. Biol Res 2025; 58:15. [PMID: 40091035 PMCID: PMC11912783 DOI: 10.1186/s40659-025-00592-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Pancreatic cancer is among the most aggressive and malignant tumors and is a leading cause of cancer-related mortality. It is characterized by its metabolic Warburg effect and glucose dependence. Aerobic glycolysis is a key feature of metabolic reprogramming in cancer cells. This study investigates the combined effect of metformin and FX11, hypothesizing that disrupting cancer cell energetics through complementary mechanisms may result in a synergistic therapeutic effect. The combination of metformin and FX11 affects the axis that regulates vital functions in cancer cells; thus, the uncontrolled growth of tumor cells, especially those that use a lactose-dependent energy pathway, can be controlled. Several in vitro experiments were conducted to evaluate this hypothesis. PANC-1 cell proliferation was assessed using an MTS assay, lactate levels were measured via an LDH assay, and apoptosis was determined using a flow cytometry-based PE-annexin V assay. The downstream effects of metformin and FX11 treatment were evaluated via western blot analysis. RESULTS The findings of this study revealed that metformin and FX11 significantly decreased the viability of PANC-1 cells when used in combination, and this effect was achieved by significantly affecting the energy mechanism of the cells through the AMPKα axis. Furthermore, the lactate levels in PANC1 cells co-treated with metformin and FX11 were significantly decreased, while the increased cellular stress led the cells to apoptosis. CONCLUSIONS Compared with metformin treatment alone, the combination treatment of metformin and FX11 stimulates cellular stress in pancreatic cancer and targets various energy processes that encourage cancer cells to undergo apoptosis. This study provides a novel therapeutic strategy for the treatment of pancreatic cancer.
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Affiliation(s)
- Melike Bayindir-Bilgic
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey
| | - Ezgi Duman
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Deniz Turgut
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Ayse Naz Kadikoylu
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Nur Ekimci-Gurcan
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Biruni University, Istanbul, Turkey
| | - Utku Ozbey
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey
| | - Aysegul Kuskucu
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Omer F Bayrak
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey.
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey.
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Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
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Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
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Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
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3
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Biswal N, Harish R, Roshan M, Samudrala S, Jiao X, Pestell RG, Ashton AW. Role of GPCR Signaling in Anthracycline-Induced Cardiotoxicity. Cells 2025; 14:169. [PMID: 39936961 PMCID: PMC11817789 DOI: 10.3390/cells14030169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/27/2024] [Accepted: 11/27/2024] [Indexed: 02/13/2025] Open
Abstract
Anthracyclines are a class of chemotherapeutics commonly used to treat a range of cancers. Despite success in improving cancer survival rates, anthracyclines have dose-limiting cardiotoxicity that prevents more widespread clinical utility. Currently, the therapeutic options for these patients are limited to the iron-chelating agent dexrazoxane, the only FDA-approved drug for anthracycline cardiotoxicity. However, the clinical use of dexrazoxane has failed to replicate expectations from preclinical studies. A limited list of GPCRs have been identified as pathogenic in anthracycline-induced cardiotoxicity, including receptors (frizzled, adrenoreceptors, angiotensin II receptors) previously implicated in cardiac remodeling in other pathologies. The RNA sequencing of iPSC-derived cardiac myocytes from patients has increased our understanding of the pathogenic mechanisms driving cardiotoxicity. These data identified changes in the expression of novel GPCRs, heterotrimeric G proteins, and the regulatory pathways that govern downstream signaling. This review will capitalize on insights from these experiments to explain aspects of disease pathogenesis and cardiac remodeling. These data provide a cornucopia of possible unexplored potential pathways by which we can reduce the cardiotoxic side effects, without compromising the anti-cancer effects, of doxorubicin and provide new therapeutic options to improve the recovery and quality of life for patients undergoing chemotherapy.
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Affiliation(s)
- Nimish Biswal
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Ritika Harish
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
| | - Minahil Roshan
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Sathvik Samudrala
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
| | - Xuanmao Jiao
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
| | - Richard G. Pestell
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
- The Wistar Institute, Philadelphia, PA 19104, USA
| | - Anthony W. Ashton
- School of Medicine, Xavier University at Aruba, Oranjestad, Aruba (X.J.); (R.G.P.)
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA;
- Division of Perinatal Research, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW 2065, Australia
- Division of Cardiovascular Medicine, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
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Shahrokhi Nejad S, Razi S, Rezaei N. The role of AMPK in pancreatic cancer: from carcinogenesis to treatment. Clin Transl Oncol 2025; 27:70-82. [PMID: 38926257 DOI: 10.1007/s12094-024-03572-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Pancreatic cancer has doubled over the previous two decades. Routine therapies are becoming incredibly resistant and failing to compensate for the burden caused by this aggressive neoplasm. As genetic susceptibility has always been a highlighted concern for this disease, identifying the molecular pathways involved in the survival and function of pancreatic cancer cells provides insight into its variant etiologies, one of which is the role of AMPK. This regulating factor of cell metabolism is crucial in the homeostasis and growth of the cell. Herein, we review the possible role of AMPK in pancreatic cancer while considering its leading effects on glycolysis and autophagy. Then, we assess the probable therapeutic agents that have resulted from the suggested pathways. Studying the underlying genetic changes in pancreatic cancer provides a chance to detect and treat patients suffering from advanced stages of the disease, and those who have given up their hope on conventional therapies can gain an opportunity to combat this cancer.
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Affiliation(s)
- Shahrzad Shahrokhi Nejad
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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5
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Mandal AK, Merriman TR, Choi HK, Mount DB. Caffeine Inhibits Both Basal and Insulin-Activated Urate Transport. Arthritis Rheumatol 2024; 76:1658-1669. [PMID: 38932509 PMCID: PMC11562663 DOI: 10.1002/art.42940] [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: 11/15/2023] [Revised: 05/22/2024] [Accepted: 06/26/2024] [Indexed: 06/28/2024]
Abstract
OBJECTIVE Caffeine, an adenosine receptor antagonist, is a potent central nervous system stimulant that also impairs insulin signaling. Recent studies have suggested that coffee consumption lowers serum urate (SU) and protects against gout by unknown mechanisms. We hypothesized that caffeine lowers SU by affecting activity of urate transporters. METHODS We examined the effect of caffeine and adenosine on basal and insulin stimulation of net 14C-urate uptake in the human renal proximal tubule cell line PTC-05 and on individual urate transporters expressed in Xenopus laevis oocytes. RESULTS We found that caffeine and adenosine efficiently inhibited both basal and insulin stimulation of net 14C-urate uptake mediated by endogenous urate transporters in PTC-05 cells. In oocytes expressing individual urate transporters, caffeine (>0.2 mM) more efficiently inhibited the basal urate transport activity of GLUT9 isoforms, OAT4, OAT1, OAT3, NPT1, ABCG2, and ABCC4 than did adenosine without significantly affecting URAT1 and OAT10. However, unlike adenosine, caffeine at lower concentrations (<0.2 mM) very effectively inhibited insulin activation of urate transport activity of GLUT9, OAT10, OAT1, OAT3, NPT1, ABCG2, and ABCC4 by blocking activation of Akt and extracellular signal-regulated kinase. CONCLUSION We postulate that inhibition of urate transport activity of the re-absorptive transporters GLUT9, OAT10, and OAT4 by caffeine is a key mechanism in its urate-lowering effects. Additionally, the ability of caffeine to block insulin-activated urate transport by GLUT9a and OAT10 suggests greater relative inhibition of these transporters in hyperinsulinemia.
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Affiliation(s)
- Asim K. Mandal
- Renal Divisions, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Tony R. Merriman
- Division of Rheumatology and Clinical Immunology, University of Alabama, Birmingham AL
| | - Hyon K. Choi
- Division of Rheumatology, Massachusetts General Hospital, Harvard Medical School, Boston MA
| | - David B. Mount
- Renal Divisions, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Renal Divisions, VA Boston Healthcare System, Harvard Medical School, Boston, MA
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6
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Zarei B, Akrami M, Rezaei N, Mahdavi M, Kamankesh M, Haririan I, Asadi M, Navaei-Nigjeh M. A doxycycline-loaded microfiber of poly-metformin/PCL for eradicating melanoma stem cells. Int J Pharm 2024; 660:124358. [PMID: 38897492 DOI: 10.1016/j.ijpharm.2024.124358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/09/2024] [Accepted: 06/16/2024] [Indexed: 06/21/2024]
Abstract
Nowadays, electrospun fibrous mats are used as drug delivery systems for loading of potential drugs in order to kill cancer cells. In the study, a skin patch for treating melanoma cancer after surgery was made using polycaprolactone and polymetformin microfibers that were loaded with doxycycline (PolyMet/PCL@DOX), an anti-cancer stem cell agent. The morphology, structure, mechanical characteristics, swelling, and porosity of the electrospun microfibers were examined. Drug release andanticancereffectiveness of PolyMet/PCL@DOXwas evaluated against A375 melanoma cancer stem cells using the MTS, Flow cytometry, colony formation and CD44 expression assays. Scanning electron microscopy (SEM) verified the micro fibrous structure with a diameter of about 2.31 µm. The porosity and swelling percentages for microfibers was 73.5 % and 2.9 %, respectively. The tensile strength at the breaking point was equal to 3.84 MPa. The IC50 of PolyMet/PCL@DOX was 7.4 μg/mL. The survival rate of A375 cells after 72 h of PolyMet/PCL@DOX treatment was 43.9 %. The colony formation capacity of A375 cells decreased after PolyMet/PCL@DOX treatment. The level of CD44 expression in the PolyMet/PCL@DOX group decreased compared to the control group. Generally, PolyMet/PCL@DOX microfibers can be a promising candidate as a patch after surgery to eradicate cancer stem cells, effectively.
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Affiliation(s)
- Behnoosh Zarei
- School of Pharmacy, International Campus, Tehran University of Medical Sciences Tehran, Iran
| | - Mohammad Akrami
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Institute of Biomaterials, University of Tehran & Tehran University of Medical Sciences (IBUTUMS), Tehran, Iran.
| | - Niloufar Rezaei
- Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Mohammad Mahdavi
- Endocrinology & Metabolism Research Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Mojtaba Kamankesh
- Department of Polymer Chemistry, School of Chemistry, College of Science, University of Tehran, Iran
| | - Ismaeil Haririan
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Institute of Biomaterials, University of Tehran & Tehran University of Medical Sciences (IBUTUMS), Tehran, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mehdi Asadi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
| | - Mona Navaei-Nigjeh
- Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
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7
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Zamanian MY, Golmohammadi M, Yumashev A, Hjazi A, Toama MA, AbdRabou MA, Gehlot A, Alwaily ER, Shirsalimi N, Yadav PK, Moriasi G. Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways. Cell Biochem Funct 2024; 42:e4071. [PMID: 38863255 DOI: 10.1002/cbf.4071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/25/2024] [Accepted: 06/02/2024] [Indexed: 06/13/2024]
Abstract
Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mariam Alaa Toama
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Anita Gehlot
- Department of Electronics & Communication Engineering, Uttaranchal Institute of Technology, Uttaranchal University, Dehradun, India
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Niyousha Shirsalimi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Pankaj Kumar Yadav
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, India
| | - Gervason Moriasi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Mount Kenya University, Thika, Kenya
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Wang Y, Ge W, Xue S, Cui J, Zhang X, Mao T, Xu H, Li S, Ma J, Yue M, Shentu D, Wang L. Cuproptosis-related lncRNAs are correlated with tumour metabolism and immune microenvironment and predict prognosis in pancreatic cancer patients. IET Syst Biol 2023; 17:174-186. [PMID: 37341253 PMCID: PMC10439495 DOI: 10.1049/syb2.12068] [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: 11/10/2022] [Revised: 06/05/2023] [Accepted: 06/09/2023] [Indexed: 06/22/2023] Open
Abstract
Cuproptosis is a novel cell death pathway, and the regulatory mechanism in pancreatic cancer (PC) is unclear. The authors aimed to figure out whether cuproptosis-related lncRNAs (CRLs) could predict prognosis in PC and the underlying mechanism. First, the prognostic model based on seven CRLs screened by the least absolute shrinkage and selection operator Cox analysis was constructed. Following this, the risk score was calculated for pancreatic cancer patients and divided patients into high and low-risk groups. In our prognostic model, PC patients with higher risk scores had poorer outcomes. Based on several prognostic features, a predictive nomogram was established. Furthermore, the functional enrichment analysis of differentially expressed genes between risk groups was performed, indicating that endocrine and metabolic pathways were potential regulatory pathways between risk groups. TP53, KRAS, CDKN2A, and SMAD4 were dominant mutated genes in the high-risk group and tumour mutational burden was positively correlated with the risk score. Finally, the tumour immune landscape indicated patients in the high-risk group were more immunosuppressive than that in the low-risk group, with lower infiltration of CD8+ T cells and higher M2 macrophages. Above all, CRLs can be applied to predict PC prognosis, which is closely correlated with the tumour metabolism and immune microenvironment.
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Affiliation(s)
- Yanling Wang
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Weiyu Ge
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Shengbai Xue
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jiujie Cui
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Xiaofei Zhang
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Tiebo Mao
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Haiyan Xu
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Shumin Li
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jingyu Ma
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ming Yue
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Daiyuan Shentu
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Liwei Wang
- Department of OncologyRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Cancer InstituteShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesDepartment of OncologyShanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
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Sinnett-Smith J, Torres-Marquez ME, Chang JK, Shimizu Y, Hao F, Martin MG, Rozengurt E. Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids. Am J Physiol Cell Physiol 2023; 324:C807-C820. [PMID: 36779664 PMCID: PMC10042602 DOI: 10.1152/ajpcell.00286.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 01/10/2023] [Accepted: 01/10/2023] [Indexed: 02/14/2023]
Abstract
We examined the impact of statins on protein kinase D (PKD) activation by G protein-coupled receptor (GPCR) agonists. Treatment of intestinal IEC-18 cells with cerivastatin inhibited PKD autophosphorylation at Ser916 induced by angiotensin II (ANG II) or vasopressin in a dose-dependent manner with half-maximal inhibition at 0.2 µM. Cerivastatin treatment inhibited PKD activation stimulated by these agonists for different times (5-60 min) and blunted HDAC5 phosphorylation, a substrate of PKD. Other lipophilic statins, including simvastatin, atorvastatin, and fluvastatin also prevented PKD activation in a dose-dependent manner. Using IEC-18 cell lines expressing PKD1 tagged with EGFP (enhanced green fluorescent protein), cerivastatin or simvastatin blocked GPCR-mediated PKD1-EGFP translocation to the plasma membrane and its subsequent nuclear accumulation. Similar results were obtained in IEC-18 cells expressing PKD3-EGFP. Mechanistically, statins inhibited agonist-dependent PKD activation rather than acting directly on PKD catalytic activity since exposure to cerivastatin or simvastatin did not impair PKD autophosphorylation or PKD1-EGFP membrane translocation in response to phorbol dibutyrate, which bypasses GPCRs and directly stimulates PKC and PKD. Furthermore, cerivastatin did not inhibit recombinant PKD activity determined via an in vitro kinase assay. Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds), and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells.
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Affiliation(s)
- James Sinnett-Smith
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
- VA Greater Los Angeles Health Care System, Los Angeles, California, United States
| | - M Eugenia Torres-Marquez
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
| | - Jen-Kuan Chang
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
| | - Yuki Shimizu
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
| | - Fang Hao
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
| | - Martin G Martin
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
- VA Greater Los Angeles Health Care System, Los Angeles, California, United States
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10
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Orchard SG, Lockery JE, Broder JC, Ernst ME, Espinoza S, Gibbs P, Wolfe R, Polekhina G, Zoungas S, Loomans-Kropp HA, Woods RL. Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes. JNCI Cancer Spectr 2023; 7:pkad017. [PMID: 36857596 PMCID: PMC10042437 DOI: 10.1093/jncics/pkad017] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 02/06/2023] [Accepted: 02/20/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND Metformin and aspirin are commonly co-prescribed to people with diabetes. Metformin may prevent cancer, but in older people (over 70 years), aspirin has been found to increase cancer mortality. This study examined whether metformin reduces cancer mortality and incidence in older people with diabetes; it used randomization to 100 mg aspirin or placebo in the ASPirin in Reducing Events in the Elderly (ASPREE) trial to quantify aspirin's impact on metformin users. METHODS Analysis included community-dwelling ASPREE participants (aged ≥70 years, or ≥65 years for members of US minority populations) with diabetes. Diabetes was defined as a fasting blood glucose level greater than 125 mg/dL, self-report of diabetes, or antidiabetic medication use. Cox proportional hazards regression models were used to analyze the association of metformin and a metformin-aspirin interaction with cancer incidence and mortality, with adjustment for confounders. RESULTS Of 2045 participants with diabetes at enrollment, 965 were concurrently using metformin. Metformin was associated with a reduced cancer incidence risk (adjusted hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.51 to 0.90), but no conclusive benefit for cancer mortality (adjusted HR = 0.72, 95% CI = 0.43 to 1.19). Metformin users randomized to aspirin had greater risk of cancer mortality compared with placebo (HR = 2.53, 95% CI = 1.18 to 5.43), but no effect was seen for cancer incidence (HR = 1.11, 95% CI = 0.75 to 1.64). The possible effect modification of aspirin on cancer mortality, however, was not statistically significant (interaction P = .11). CONCLUSIONS In community-dwelling older adults with diabetes, metformin use was associated with reduced cancer incidence. Increased cancer mortality risk in metformin users randomized to aspirin warrants further investigation. ASPREE TRIAL REGISTRATION ClinicalTrials.gov ID NCT01038583.
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Affiliation(s)
- Suzanne G Orchard
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Jessica E Lockery
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
- Translational Immunology and Nanotechnology Research Theme, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
- Department of Internal Medicine, Division of Cancer Prevention and Control, Ohio State University, Columbus, OH, USA
| | - Jonathan C Broder
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Michael E Ernst
- Department of Pharmacy Practice and Science, College of Pharmacy and Department of Family Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
| | - Sara Espinoza
- Division of Geriatrics, Gerontology and Palliative Medicine, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, and Geriatrics Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Peter Gibbs
- The Walter & Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Melbourne, VIC, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Rory Wolfe
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Galina Polekhina
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Sophia Zoungas
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
| | - Holli A Loomans-Kropp
- Department of Internal Medicine, Division of Cancer Prevention and Control, Ohio State University, Columbus, OH, USA
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA
| | - Robyn L Woods
- School of Public Health and Preventive Medicine, Monash University, Melbourne,VIC, Australia
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11
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Cannabinoids Transmogrify Cancer Metabolic Phenotype via Epigenetic Reprogramming and a Novel CBD Biased G Protein-Coupled Receptor Signaling Platform. Cancers (Basel) 2023; 15:cancers15041030. [PMID: 36831374 PMCID: PMC9954791 DOI: 10.3390/cancers15041030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/29/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
The concept of epigenetic reprogramming predicts long-term functional health effects. This reprogramming can be activated by exogenous or endogenous insults, leading to altered healthy and different disease states. The exogenous or endogenous changes that involve developing a roadmap of epigenetic networking, such as drug components on epigenetic imprinting and restoring epigenome patterns laid down during embryonic development, are paramount to establishing youthful cell type and health. This epigenetic landscape is considered one of the hallmarks of cancer. The initiation and progression of cancer are considered to involve epigenetic abnormalities and genetic alterations. Cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer development, including DNA methylation, histone modifications, nucleosome positioning, non-coding RNAs, and microRNA expression. Endocannabinoids are natural lipid molecules whose levels are regulated by specific biosynthetic and degradative enzymes. They bind to and activate two primary cannabinoid receptors, type 1 (CB1) and type 2 (CB2), and together with their metabolizing enzymes, form the endocannabinoid system. This review focuses on the role of cannabinoid receptors CB1 and CB2 signaling in activating numerous receptor tyrosine kinases and Toll-like receptors in the induction of epigenetic landscape alterations in cancer cells, which might transmogrify cancer metabolism and epigenetic reprogramming to a metastatic phenotype. Strategies applied from conception could represent an innovative epigenetic target for preventing and treating human cancer. Here, we describe novel cannabinoid-biased G protein-coupled receptor signaling platforms (GPCR), highlighting putative future perspectives in this field.
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12
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Shete MB, Deshpande AS, Shende PK. Nanostructured lipid carrier-loaded metformin hydrochloride: Design, optimization, characterization, assessment of cytotoxicity and ROS evaluation. Chem Phys Lipids 2023; 250:105256. [PMID: 36372117 DOI: 10.1016/j.chemphyslip.2022.105256] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/29/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Metformin hydrochloride (MET) is commonly used in diabetes treatment. Recently, it has gained interest for its anticancer potential against a wide range of cancers. Owing to its hydrophilic nature, the delivery and clinical actions of MET are limited. Therefore, the present work aims to develop MET-encapsulated NLCs using the hot-melt emulsification and probe-sonication method. The optimization was accomplished by 33 BB design wherein lipid ratio, surfactant concentration, and sonication time were independent variables while the PS (nm), PDI, and EE (%) were dependent variables. The PS, PDI, % EE and ZP of optimized GMSMET-NLCs were found to be 114.9 ± 1.32 nm, 0.268 ± 0.04 %, 60.10 ± 2.23 %, and ZP - 15.76 mV, respectively. The morphological features, DSC and PXRD, and FTIR analyses suggested the confirmation of formation of the NLCs. Besides, optimized GMSMET-NLCs showed up to 88 % MET release in 24 h. Moreover, GMSMET-NLCs showed significant cell cytotoxicity against KB oral cancer cells compared with MET solution as shown by the reduction of IC50 values. Additionally, GMSMET-NLCs displayed significantly increased intracellular ROS levels suggesting the GMSMET-NLCs induced cell death in KB cells. GMSMET-NLCs can therefore be explored to deliver MET through different routes of administration for the effective treatment of oral cancer.
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Affiliation(s)
- Meghanath B Shete
- School of Pharmacy & Technology Management, SVKM'S NMIMS, Shirpur, Maharashtra, India; Department of Pharmaceutical Quality Assurance, R C Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist., Dhule 425405, Maharashtra, India
| | - Ashwini S Deshpande
- School of Pharmacy & Technology Management, SVKM'S NMIMS, Polepally SEZ, TSIIC Jadcherla, Hyderabad 509301, India
| | - Pravin K Shende
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, Vile-Parle (W), Mumbai, Maharashtra, India.
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13
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Du Y, Zhu YJ, Zhou YX, Ding J, Liu JY. Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study. MOLECULAR BIOMEDICINE 2022; 3:41. [PMID: 36484892 PMCID: PMC9733765 DOI: 10.1186/s43556-022-00108-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20-30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.
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Affiliation(s)
- Yang Du
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ya-Juan Zhu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yi-Xin Zhou
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jing Ding
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Ji-Yan Liu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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Sinnett-Smith J, Anwar T, Reed EF, Teper Y, Eibl G, Rozengurt E. Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy. Mol Cancer Ther 2022; 21:1652-1662. [PMID: 35999654 PMCID: PMC9630827 DOI: 10.1158/1535-7163.mct-21-0964] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 04/22/2022] [Accepted: 08/19/2022] [Indexed: 01/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease that is expected to become the second cause of cancer fatalities during the next decade. As therapeutic options are limited, novel targets, and agents for therapeutic intervention are urgently needed. Previously, we identified potent positive crosstalk between insulin/IGF-1 receptors and G protein-coupled (GPCR) signaling systems leading to mitogenic signaling in PDAC cells. Here, we show that a combination of insulin and the GPCR agonist neurotensin induced rapid activation of Src family of tyrosine kinases (SFK) within PANC-1 cells, as shown by FAK phosphorylation at Tyr576/577 and Tyr861, sensitive biomarkers of SFK activity within intact cells and Src416 autophosphorylation. Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, siRNA-mediated knockdown of YES1, and transfection of epitogue-tagged YAP mutants in PANC-1 and Mia PaCa-2 cancer cells, models of the aggressive squamous subtype of PDAC. Surprisingly, our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES and Src induces ERK overactivation in PDAC cells. Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor trametinib. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells and suppressed the growth of Mia PaCa-2 cells xenografted into the flank of nude mice. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g., trametinib) inhibitors in prospective clinical trials for the treatment of PDAC.
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Affiliation(s)
- James Sinnett-Smith
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
- VA Greater Los Angeles Health System
| | - Tarique Anwar
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California
| | - Yaroslav Teper
- Department of Surgery, University of California, Los Angeles, California
| | - Guido Eibl
- Department of Surgery, University of California, Los Angeles, California
| | - Enrique Rozengurt
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
- VA Greater Los Angeles Health System
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15
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Kim J, Bae YJ, Kang HT. Metformin Use May Increase Risk of Pancreatic Cancer in Diabetic Women: An Analysis of the Korean National Health Insurance Service-National Health Screening Cohort Database. Korean J Fam Med 2022; 43:327-333. [PMID: 36168905 PMCID: PMC9532184 DOI: 10.4082/kjfm.22.0005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/21/2022] [Indexed: 11/03/2022] Open
Abstract
Background: In addition to its antidiabetic effects, metformin has pleiotropic effects, such as the inhibition of carcinogenesis. This study aimed to investigate the association between metformin use and pancreatic cancer risk in the Korean National Health Insurance Service (NHIS)-National Health Screening Cohort (HEALS).Methods: Of the individuals in the Korean NHIS-HEALS, 29,271 men and 19,091 women were included in the final analysis after propensity score matching based on age, body mass index, and smoking status. The study population was categorized into three groups: metformin non-users with diabetes mellitus (DM), metformin users with DM, and non-diabetic users. A Cox proportional hazards regression model was used to examine the association between metformin use and pancreatic cancer.Results: The median follow-up period was 12.9 years. The estimated pancreatic cancer incidence was highest in metformin users with DM, regardless of sex (P<0.001), and lowest in non-diabetic men and female metformin non-users (P=0.053). The hazard ratios (95% confidence interval) for pancreatic cancer incidence in metformin users and non-diabetic individuals were 1.116 (0.648–1.923) and 0.447 (0.259–0.771) in men and 2.769 (1.003–7.642) and 1.451 (0.529–3.984) in women, respectively, after full adjustment.Conclusion: Women with diabetes using metformin are at a higher risk of pancreatic cancer than women with diabetes not using metformin. Meanwhile, men with DM using metformin have a similar risk of pancreatic cancer as men with DM not using metformin.
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Affiliation(s)
- Joungyoun Kim
- Department of Artificial Intelligence, University of Seoul, Seoul, Korea
| | - Yoon-Jong Bae
- Department of Information & Statistics, Chungbuk National University, Cheongju, Korea
| | - Hee-Taik Kang
- Department of Family Medicine, Chungbuk National University Hospital, Cheongju, Korea
- Department of Family Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
- Corresponding Author: Hee-Taik Kang Tel: +82-43-269-6301, Fax: +82-43-269-6675, E-mail:
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16
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Poman DS, Motwani L, Asif N, Patel A, Vedantam D. Pancreatic Cancer and the Obesity Epidemic: A Narrative Review. Cureus 2022; 14:e26654. [PMID: 35959181 PMCID: PMC9360631 DOI: 10.7759/cureus.26654] [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] [Accepted: 07/07/2022] [Indexed: 11/05/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most frequent causes of death. It usually affects older individuals with incidence closely approaching mortality due to its early asymptomatic feature and highly metastatic nature. Multiple risk factors such as family history, smoking, and germline mutations are associated with PC development, with obesity being one of the controllable factors. This review article focuses on the compilation of various studies to help establish a correlation between obesity or an increased body mass index and PC development. Hence, in this review, we have summarised multiple biological mechanisms of PC development induced by obesity, including insulin resistance, inflammation, beta-cell dysfunction, and oxidative stress, to prove that their correlation when combined with other factors, such as smoking, alcohol and chronic pancreatitis, may increase its risk. We have also reviewed potential diagnostic and screening techniques, such as evaluating precancerous lesions in high-risk patients and management plans discussing upcoming advances in treatment tactics such as neoadjuvant therapy, to reduce post-operative complications.
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Affiliation(s)
| | - Lakshya Motwani
- Research and Development, Smt. Nathiba Hargovandas Lakhmichand (NHL) Municipal Medical College, Ahmedabad, IND
| | - Nailah Asif
- Research, Ras Al Khaimah (RAK) College of Medical Sciences, Ras Al Khaimah, ARE
| | - Apurva Patel
- Research, Gujarat Medical Education & Research Society (GMERS) Medical College, Gotri, Vadodara, IND
| | - Deepanjali Vedantam
- Internal Medicine, Kamineni Academy of Medical Sciences and Research Center, Hyderabad, IND
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17
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High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1466991. [PMID: 35592685 PMCID: PMC9113878 DOI: 10.1155/2022/1466991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 12/21/2022]
Abstract
Objective To explore the mechanism of metformin in treating CCRCC. Methods Prospective cohort study was conducted. SOD and cyclin D in six CCRCC samples donated by volunteers were detected to compare the degree of oxidative stress injury and the status of cell proliferation. 786-0 CCRCC cells were cultured in vitro with different concentrations of metformin, and MTT assay and Transwell cell migration and wound healing assay were used to detect their proliferation and migration. After culture, SOD and cyclin D in 786-0 CCRCC cells were also detected. Results In the edge tissue, SOD was lower than in the tumor nest and normal tissue, and cyclin D was highly expressed. In grade II CCRCC, SOD was higher than in grade IV CCRCC, but cyclin D was also highly expressed in grade IV CCRCC. The cell proliferation rate and density of the metformin group were lower than the control group, while in the high-concentration metformin group, it was lower than medium- and low-concentration groups. After culture, the migration of 786-0 cells in the metformin group was significantly lower than that in the control group, the wound healing rate was decreased, and the migration and wound healing rates in the high-concentration metformin group were significantly lower than those in the medium- and low-concentration groups. However, the SOD of the metformin group was higher than the control group, but the cyclin D was lower, while the SOD was higher than medium- and low-concentration groups in the high-concentration group, but the cyclin D was lower after cultured. Conclusion High-concentration metformin can reduce oxidative stress injury, increase the expression of SOD in CCRCC, and reduce cyclin D in CCRCC to inhibit proliferation and migration, which has optimistic prospects and application value in controlling the progression of CCRCC.
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18
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Rossiter JL, Redlinger LJ, Kolar GR, Samson WK, Yosten GLC. The actions of C-peptide in HEK293 cells are dependent upon insulin and extracellular glucose concentrations. Peptides 2022; 150:170718. [PMID: 34954230 DOI: 10.1016/j.peptides.2021.170718] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 10/19/2022]
Abstract
Connecting peptide, or C-peptide, is a part of the insulin prohormone and is essential for the proper folding and processing of the mature insulin peptide. C-peptide is released from the same beta cell secretory granules as insulin in equimolar amounts. However, due to their relative stabilities in plasma, the two peptides are detected in the circulation at ratios of approximately 4:1 to 6:1 (C-peptide to insulin), depending on metabolic state. C-peptide binds specifically to human cell membranes and induces intracellular signaling cascades, likely through an interaction with the G protein coupled receptor, GPR146. C-peptide has been shown to exert protective effects against the vascular, renal, and ocular complications of diabetes. The effects of C-peptide appear to be dependent upon the presence of insulin and the absolute, extracellular concentration of glucose. In this study, we employed HEK293 cells to further examine the interactive effects of C-peptide, insulin, and glucose on cell signaling. We observed that C-peptide's cellular effects are dampened significantly when cells are exposed to physiologically relevant concentrations of both insulin and C-peptide. Likewise, the actions of C-peptide on cFos and GPR146 mRNA expressions were affected by changes in extracellular glucose concentration. In particular, C-peptide induced significant elevations in cFos expression in the setting of high (25 mmol) extracellular glucose concentration. These data indicate that future experimentation on the actions of C-peptide should control for the presence or absence of insulin and the concentration of glucose. Furthermore, these findings should be considered prior to the development of C-peptide-based therapeutics for the treatment of diabetes-associated complications.
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Affiliation(s)
- Jacqueline L Rossiter
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, Saint Louis, MO 63104, United States
| | - Lauren J Redlinger
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, Saint Louis, MO 63104, United States
| | - Grant R Kolar
- Department of Pathology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, Saint Louis, MO 63104, United States
| | - Willis K Samson
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, Saint Louis, MO 63104, United States
| | - Gina L C Yosten
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 S. Grand Boulevard, Saint Louis, MO 63104, United States.
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Rozengurt E, Eibl G. Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance. Cancers (Basel) 2021; 13:5126. [PMID: 34680275 PMCID: PMC8533944 DOI: 10.3390/cancers13205126] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.
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Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
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20
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Obesity and Pancreatic Cancer: Insight into Mechanisms. Cancers (Basel) 2021; 13:cancers13205067. [PMID: 34680216 PMCID: PMC8534007 DOI: 10.3390/cancers13205067] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Obesity is recognized as a chronic progressive disease and risk factor for many human diseases. The high and increasing number of obese people may underlie the expected increase in pancreatic cancer cases in the United States. There are several pathways discussed that link obesity with pancreatic cancer. Adipose tissue and adipose tissue-released factors may thereby play an important role. This review discusses selected mechanisms that may accelerate pancreatic cancer development in obesity. Abstract The prevalence of obesity in adults and children has dramatically increased over the past decades. Obesity has been declared a chronic progressive disease and is a risk factor for a number of metabolic, inflammatory, and neoplastic diseases. There is clear epidemiologic and preclinical evidence that obesity is a risk factor for pancreatic cancer. Among various potential mechanisms linking obesity with pancreatic cancer, the adipose tissue and obesity-associated adipose tissue inflammation play a central role. The current review discusses selected topics and mechanisms that attracted recent interest and that may underlie the promoting effects of obesity in pancreatic cancer. These topics include the impact of obesity on KRAS activity, the role of visceral adipose tissue, intrapancreatic fat, adipose tissue inflammation, and adipokines on pancreatic cancer development. Current research on lipocalin-2, fibroblast growth factor 21, and Wnt5a is discussed. Furthermore, the significance of obesity-associated insulin resistance with hyperinsulinemia and obesity-induced gut dysbiosis with metabolic endotoxemia is reviewed. Given the central role that is occupied by the adipose tissue in obesity-promoted pancreatic cancer development, preventive and interceptive strategies should be aimed at attenuating obesity-associated adipose tissue inflammation and/or at targeting specific molecules that mechanistically link adipose tissue with pancreatic cancer in obese patients.
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21
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Duarte D, Vale N. Combining repurposed drugs to treat colorectal cancer. Drug Discov Today 2021; 27:165-184. [PMID: 34592446 DOI: 10.1016/j.drudis.2021.09.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 07/19/2021] [Accepted: 09/22/2021] [Indexed: 02/08/2023]
Abstract
The drug development process, especially of antineoplastic agents, has become increasingly costly and ineffective. Drug repurposing and drug combination are alternatives to de novo drug development, being low cost, rapid, and easy to apply. These strategies allow higher efficacy, decreased toxicity, and overcoming of drug resistance. The combination of antineoplastic agents is already being applied in cancer therapy, but the combination of repurposed drugs is still under-explored in pre- and clinical development. In this review, we provide a set of pharmacological concepts focusing on drug repurposing for treating colorectal cancer (CRC) and that are relevant for the application of new drug combinations against this disease.
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Affiliation(s)
- Diana Duarte
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
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22
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Gyawali M, Venkatesan N, Ogeyingbo OD, Bhandari R, Botleroo RA, Kareem R, Ahmed R, Elshaikh AO. Magic of a Common Sugar Pill in Cancer: Can Metformin Raise Survival in Pancreatic Cancer Patients? Cureus 2021; 13:e16916. [PMID: 34367843 PMCID: PMC8343553 DOI: 10.7759/cureus.16916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the common cancers globally, with a poor survival outcome. Metformin, a popular anti-diabetic drug, has gained popularity for its use in the chemoprevention of cancer. However, results regarding the survival benefit of metformin in pancreatic cancer have been unpredictable. In this review, we aim to analyze the use of metformin in pancreatic cancer patients with pre-existing diabetes mellitus for survival benefit. We systematically conducted a literature search in PubMed, Science Direct, and Scopus databases to collect the relevant articles and reviewed them. Eventually, 11 quality appraised articles were included accessing overall survival as the primary outcome. Our results concluded that metformin can efficaciously improve survival in pancreatic cancer patients with coexisting diabetes mellitus, but the results are still incongruent. Hence, further prospective studies and clinical trials are essential to provide a strong evidence-based recommendation that will help prolong the lifespan of patients.
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Affiliation(s)
- Mallika Gyawali
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nanditha Venkatesan
- Internal Medicine, All India Institute of Medical Sciences, Raipur, IND.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Opemipo D Ogeyingbo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Saint James School of Medicine, Park Ridge, USA.,Public Health, Walden University, Minneapolis, USA
| | - Renu Bhandari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Manipal College of Medical Sciences, Pokhara, NPL
| | - Rinky A Botleroo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Roaa Kareem
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Rowan Ahmed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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23
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De Lellis L, Veschi S, Tinari N, Mokini Z, Carradori S, Brocco D, Florio R, Grassadonia A, Cama A. Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates. Cancers (Basel) 2021; 13:3946. [PMID: 34439102 PMCID: PMC8394389 DOI: 10.3390/cancers13163946] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.
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Affiliation(s)
- Laura De Lellis
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Nicola Tinari
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Zhirajr Mokini
- European Society of Anaesthesiology and Intensive Care (ESAIC) Mentorship Programme, ESAIC, 24 Rue des Comédiens, BE-1000 Brussels, Belgium;
| | - Simone Carradori
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Davide Brocco
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Rosalba Florio
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Antonino Grassadonia
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
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24
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Chen YH, Huang YC, Yang SF, Yen HH, Tsai HD, Hsieh MC, Hsiao YH. Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:1491-1503. [PMID: 33886150 DOI: 10.1002/tox.23146] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/12/2021] [Accepted: 04/02/2021] [Indexed: 06/12/2023]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 μM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 μM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.
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Affiliation(s)
- Ya-Hui Chen
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ying-Chih Huang
- Department of Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Horng-Der Tsai
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Chia Hsieh
- Intelligent Diabetes Metabolism and Exercise Center, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Hsuan Hsiao
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
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25
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Eibl G, Rozengurt E. Metformin: review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 2021; 40:865-878. [PMID: 34142285 DOI: 10.1007/s10555-021-09977-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma continues to be a lethal disease, for which efficient treatment options are very limited. Increasing efforts have been taken to understand how to prevent or intercept this disease at an early stage. There is convincing evidence from epidemiologic and preclinical studies that the antidiabetic drug metformin possesses beneficial effects in pancreatic cancer, including reducing the risk of developing the disease and improving survival in patients with early-stage disease. This review will summarize the current literature about the epidemiological data on metformin and pancreatic cancer as well as describe the preclinical evidence illustrating the anticancer effects of metformin in pancreatic cancer. Underlying mechanisms and targets of metformin will also be discussed. These include direct effects on transformed pancreatic epithelial cells and indirect, systemic effects on extra-pancreatic tissues.
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Affiliation(s)
- Guido Eibl
- Department of Surgery, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA.
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA
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26
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Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol 2021; 27:1883-1904. [PMID: 34007128 PMCID: PMC8108031 DOI: 10.3748/wjg.v27.i17.1883] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.
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Affiliation(s)
- Ademar Dantas Cunha Júnior
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Felipe Osório Costa
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
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27
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Zhang AM, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in Obesity, Inflammation, and Cancer. Diabetes Metab J 2021; 45:285-311. [PMID: 33775061 PMCID: PMC8164941 DOI: 10.4093/dmj.2020.0250] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.
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Affiliation(s)
- Anni M.Y. Zhang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth A. Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Janel L. Kopp
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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28
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Yenmiş G, Beşli N, Yaprak Saraç E, Hocaoğlu Emre FS, Şenol K, Kanıgür G. Metformin promotes apoptosis in primary breast cancer cells by downregulation of cyclin D1 and upregulation of P53 through an AMPK-alpha independent mechanism. Turk J Med Sci 2021; 51:826-834. [PMID: 33350292 PMCID: PMC8203121 DOI: 10.3906/sag-1908-112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 12/17/2020] [Indexed: 12/25/2022] Open
Abstract
Background/aim In the present study we aimed to figure out the effect of metformin on the expression of AMPK-alpha, cyclin D1, and Tp53, and apoptosis in primary breast cancer cells (PBCCs). Materials and methods PBCCs were treated with two doses of metformin (0 mM, 25 mM). Proliferation was determined by BrdU as- say. Real-time PCR was used to assess AMPK-alpha, cyclin D1, and Tp53 gene expressions; apoptotic indexes of PBCCs were analyzed using flow-cytometry. Results Twenty-four–hour incubation with 25 mM metformin reduced the proliferation of PBCCs. AMPK-alpha gene expression in PBCCs was not affected by 25 mM metformin treatment compared with the control group. PBCCs treated with 25 mM metformin had lower cyclin D1 expression compared with nontreated cells; however, the difference was not statistically significant. Twenty-five mil- limolar dose of metformin increased p53 expression significantly compared with the nontreated group. The high concentration of met- formin elevated the number of annexin V-positive apoptotic cells, and the increase in the apoptotic index was statistically significant. Conclusion Metformin can modulate cyclin D1 and p53 expression through AMPK-alpha-independent mechanism in breast cancer cells, leading to cell proliferation inhibition and apoptosis induction.
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Affiliation(s)
- Güven Yenmiş
- Department of Medical Biology, Faculty of Medicine, Biruni University, İstanbul, Turkey
| | - Nail Beşli
- Department of Medical Biology, Faculty of Medicine, Sağlık Bilimleri University, İstanbul, Turkey
| | - Elif Yaprak Saraç
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, İstanbul Technical University, İstanbul, Turkey
| | - Fatma Sinem Hocaoğlu Emre
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Beykent University, İstanbul, Turkey
| | - Kazım Şenol
- Department of General Surgery, Faculty of Medicine, Bursa Uludağ University, Bursa, Turkey
| | - Gönül Kanıgür
- Department of Molecular Biology and Genetics, Faculty of Medicine, Istanbul Aydın University, İstanbul, Turkey
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29
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Adalsteinsson JA, Muzumdar S, Waldman R, Wu R, Ratner D, Feng H, Ungar J, Silverberg JI, Olafsdottir GH, Kristjansson AK, Tryggvadottir L, Jonasson JG. Metformin is associated with decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland. J Am Acad Dermatol 2021; 85:56-61. [PMID: 33610593 DOI: 10.1016/j.jaad.2021.02.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/11/2021] [Accepted: 02/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Metformin has anticarcinogenic properties and is also known to inhibit the sonic hedgehog pathway, but population-based studies analyzing the potential protective effect for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are needed. OBJECTIVES To delineate the association between metformin use and invasive SCC, SCC in situ (SCCis), and BCC. METHODS A population-based case-control study design was employed using all 6880 patients diagnosed in Iceland between 2003-2017 with first-time BCC, SCCis, or invasive SCC, and 69,620 population controls. Multivariate odds ratios (ORs) were calculated using conditional logistic regression. RESULTS Metformin was associated with a lower risk of developing BCC (OR, 0.71; 95% confidence interval [CI], 0.61-0.83), even at low doses. No increased risk of developing SCC was observed. SCCis risk was mildly elevated in the 501-1500 daily dose unit category (OR, 1.40; 95% CI, 1.00-1.96). LIMITATIONS This study was retrospective in nature with the inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. CONCLUSION Metformin is associated with decreased risk of BCC development, even at low doses. Metformin might have potential as a chemoprotective agent for patients at high risk of BCC, although this will need confirmation in future studies.
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Affiliation(s)
- Jonas A Adalsteinsson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Dermatology, University of Connecticut, Farmington, Connecticut.
| | - Sonal Muzumdar
- Department of Dermatology, University of Connecticut, Farmington, Connecticut
| | - Reid Waldman
- Department of Dermatology, University of Connecticut, Farmington, Connecticut
| | - Rong Wu
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut
| | - Désirée Ratner
- Department of Dermatology, New York University Langone Health, New York, New York
| | - Hao Feng
- Department of Dermatology, University of Connecticut, Farmington, Connecticut
| | - Jonathan Ungar
- Mount Sinai Department of Dermatology, New York, New York
| | - Jonathan I Silverberg
- The George Washington University School of Medicine and Health Sciences, Washington, DC
| | | | | | - Laufey Tryggvadottir
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Icelandic Cancer Registry, Reykjavik, Iceland
| | - Jon Gunnlaugur Jonasson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Pathology, Landspitali National-University Hospital, Reykjavik, Iceland
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30
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Guo J, Liu J, Qie H, Zhao F, Niu CH. Efficient synthesis strategy of folate-modified carboxymethyl chitosan/CaCO 3 hybrid nanospheres and their drug-carrying and sustained release properties. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2021; 32:799-812. [PMID: 33428541 DOI: 10.1080/09205063.2020.1870258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Folate-modified carboxymethyl chitosan (FCMC) was made by folate acid as targeted group and attaching folate to carboxymethyl chitosan, and then, targeted FCMC/CaCO3 hybrid nanosphere were formed by self-assembly of calcium carbonate in FCMC solution. The physicochemical properties of the nanospheres were investigated by Fourier transform infrared spectroscopy, X-ray diffraction analysis, Brunauer-Emmett-Teller measurement and thermogravimetric analysis (TGA). The results showed that the FCMC/CaCO3 hybrid nanospheres were composed of calcite, vaterite and polysaccharides, and the content of organic compounds was 12.17%. Also, the structure performance of the hybrid nanospheres was analyzed. Besides, the effects of the hybrid nanospheres on the encapsulation efficiency, the drug loading content and the release behavior were also analyzed with the metformin (MET) as a model drug. Scanning electron microscope, Zeta potential analysis and UV-Vis were used to characterize the hybrid nanospheres. Under the conditions of FCMC/Ca2+ molar ratio of 4: 1 and reaction for 24 h, the achieved results showed that the spherical aggregates with regular morphology were obtained and the average particle size of the nanospheres was 207 nm. The specific surface area of the hybrid nanosphere is 27.06 m2·g-1 and the average pore diameter of the sample is 3.84 nm, indicating the presence of mesoporous structure in the sample. This mesoporous structure can supply potential space for adsorption of anticancer drugs. Additionally, the surface charge of the nanoparticles was positive and the entrapment efficiency was 83.32%. The hybrid nanospheres have a capability of effective pH-sensitivity controlled drug release. All the drug loaded hybrid nanospheres successfully sustained the release of MET at pH 7.4, only about 44.58% of the drug released in 6 days. While under acidic condition (pH 5.0) drug release was significantly accelerated, being over 98.85% of the drug released. The hybrid nanospheres demonstrated an excellent smart drug delivery behavior.
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Affiliation(s)
- Jianfeng Guo
- School of Chemical Engineering and Technology, North University of China Taiyuan, Shanxi, China.,Department of Chemical and Biological Engineering, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Juhui Liu
- School of Chemical Engineering and Technology, North University of China Taiyuan, Shanxi, China
| | - Haoran Qie
- School of Chemical Engineering and Technology, North University of China Taiyuan, Shanxi, China
| | - Feng Zhao
- School of Chemical Engineering and Technology, North University of China Taiyuan, Shanxi, China
| | - Catherine Hui Niu
- Department of Chemical and Biological Engineering, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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31
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Mao W, Mai J, Peng H, Wan J, Sun T. YAP in pancreatic cancer: oncogenic role and therapeutic strategy. Theranostics 2021; 11:1753-1762. [PMID: 33408779 PMCID: PMC7778590 DOI: 10.7150/thno.53438] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), remains a fatal disease with few efficacious treatments. The Hippo signaling pathway, an evolutionarily conserved signaling module, plays critical roles in tissue homeostasis, organ size control and tumorigenesis. The transcriptional coactivator yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is associated with various human cancers including PDAC. Considering its importance in cancer, YAP is emerging as a promising therapeutic target. In this review, we summarize the current understanding of the oncogenic role and regulatory mechanism of YAP in PDAC, and the potential therapeutic strategies targeting YAP.
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Lee Y, Joo J, Lee YJ, Lee EK, Park S, Kim TS, Lee SH, Kim SY, Wie GA, Park M, Kim MJ, Lee JS, Han JY. Randomized phase II study of platinum-based chemotherapy plus controlled diet with or without metformin in patients with advanced non-small cell lung cancer. Lung Cancer 2020; 151:8-15. [PMID: 33278671 DOI: 10.1016/j.lungcan.2020.11.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/30/2020] [Accepted: 11/04/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Accumulating evidence indicates anti-diabetic drug metformin has anti-cancer effect by controlling cancer metabolism. We evaluated whether addition of metformin to chemotherapy improved survival of lung cancer patients. MATERIALS AND METHODS This randomized phase II study enrolled 164 patients with chemo-native, EGFR-ALK wild-type, stage IIIB/IV non-small-cell lung cancer (NSCLC). Patients were randomized to receive chemotherapy either with metformin (1000 mg twice daily) or alone every 3 weeks for six cycles. The patients received gemcitabine (1000 mg/m2) on days 1 and 8 and carboplatin (5 area under the curve) on day 1. Exploratory studies included serum metabolic panels, positron-emission tomography (PET) imaging, and genetic mutation tests for metabolism-related genes. RESULTS Metformin group showed no significant difference in the risk of progression and death compared to control group (progression: hazard ratio [HR] = 1.01 [95% confidence interval (CI) = 0.72 - 1.42], P = 0.935; death: HR = 0.95 [95% CI = 0.67-1.34], P = 0.757). Squamous cell carcinoma (SqCC) had significantly higher fluorodeoxyglucose (FDG) uptake on baseline PET image than non-SqCC NSCLC (P = 0.004). In the SqCC with high FDG uptake, the addition of metformin significantly decreased the risk of progression and death (progression: HR = 0.31 [95% CI = 0.12-0.78], P = 0.013; death: HR = 0.42 [95% CI = 0.18-0.94], P = 0.035). The HDL-cholesterol level was significantly increased after the treatment in metformin group compared to control group (P = 0.011). The metformin group showed no survival benefit in the patients with hyperinsulinemia or patients whose insulin level was decreased after treatment. CONCLUSIONS Addition of metformin to chemotherapy provided no survival benefit in unselected NSCLC patients. However, it significantly improved the survival of the selected patients with SqCC showing high FDG uptake. It suggests metformin shows the synergistic anti-tumor effect in the tumor which are highly dependent on glucose metabolism.
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Affiliation(s)
- Youngjoo Lee
- Center for Lung Cancer, National Cancer Center Korea, Goyang, Republic of Korea
| | - Jungnam Joo
- Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, USA
| | - You Jin Lee
- Division of Endocrinology, Department of Internal Medicine, National Cancer Center Korea, Goyang, Republic of Korea
| | - Eun Kyung Lee
- Division of Endocrinology, Department of Internal Medicine, National Cancer Center Korea, Goyang, Republic of Korea
| | - Sohyun Park
- Department of Nuclear Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Tae-Sung Kim
- Department of Nuclear Medicine, National Cancer Center Korea, Goyang, Republic of Korea
| | - Soo-Hyun Lee
- Department of Radiology, National Cancer Center Korea, Goyang, Republic of Korea
| | - So Young Kim
- Department of Clinical Nutrition, National Cancer Center Korea, Goyang, Republic of Korea
| | - Gyung-Ah Wie
- Department of Clinical Nutrition, National Cancer Center Korea, Goyang, Republic of Korea
| | - Minjoung Park
- Center for Lung Cancer, National Cancer Center Korea, Goyang, Republic of Korea
| | - Mi-Jung Kim
- Division of Medical Oncology, Department of Internal Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon, Republic of Korea
| | - Jin Soo Lee
- Center for Lung Cancer, National Cancer Center Korea, Goyang, Republic of Korea
| | - Ji-Youn Han
- Center for Lung Cancer, National Cancer Center Korea, Goyang, Republic of Korea.
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Wu Z, Qu B, Huang X, Song Y, Gao P, Shi J, Zhou C, Wang Z. The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1404. [PMID: 33313149 PMCID: PMC7723600 DOI: 10.21037/atm-20-4441] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Recently, there have been several randomized clinical trials (RCTs) conducted to evaluate the efficacy and safety of metformin plus standard treatment in inoperable cancer patients. Our meta-analysis aimed to assess the efficacy of metformin in combination with standard treatment in inoperable cancer patients. Methods PubMed and Embase databases were systematically searched for relevant RCTs investigating the efficacy of adding metformin to standard treatment for cancer patients. The pooled relative risk (RR) for tumor response and safety was calculated to assess the efficacy of combining metformin with standard treatment. Meta-analysis was subsequently performed to pool the hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). Results Ten RCTs comprising 1033 patients were included in our current meta-analysis. In patients with breast cancer, results of meta-analysis showed that the addition of metformin to standard treatment was beneficial to objective response rate (ORR) with 30.3% (33/109) in the metformin plus standard treatment group and 16.1% (18/112) in the placebo group (RR 1.92, 95% CI: 1.19–3.10, P=0.008). OS and PFS were not significantly improved in patients who received metformin plus standard treatment compared with those who received placebo plus standard treatment (OS: HR 1.02, 95% CI: 0.71–1.46, P=0.916; PFS: HR 1.14, 95% CI: 0.86–1.50, P=0.366). For lung cancer patients, meta-analysis results showed adding metformin to standard treatment could benefit ORR (metformin 65.3% vs. placebo 54.6%, RR 1.22, 95% CI: 1.03–1.43, P=0.018) with no significant survival benefit in the metformin group. For patients with pancreatic cancer, the pooled ORR was 17.6% (16/91) in metformin plus standard treatment group and 20% (18/90) in the placebo group, indicating metformin did not benefit ORR (RR 0.85, 95% CI: 0.49–1.49, P=0.576). Besides, the addition of metformin to standard treatment did not increase the incidence rate of adverse effects. Conclusions Our results indicated that addition of metformin to standard treatment was beneficial to ORR in inoperable breast or lung cancer patients without increasing the incidence of adverse effects. However, adding metformin to standard treatment could not benefit OS and PFS.
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Affiliation(s)
- Zhonghua Wu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Bicheng Qu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Cen Zhou
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, Zabuliene L, Smailyte G. Cohort Study of Antihyperglycemic Medication and Pancreatic Cancer Patients Survival. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17176016. [PMID: 32824907 PMCID: PMC7503289 DOI: 10.3390/ijerph17176016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/06/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022]
Abstract
Background: We assessed the association between the use of metformin and other antihyperglycemic medications on overall survival in diabetic patients with pancreatic cancer. Methods: Patients with pancreatic cancer and diabetes between 2000 and 2015 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database. Cohort members were classified into six groups according to type 2 diabetes mellitus treatment: sulfonylurea monotherapy; metformin monotherapy; insulin monotherapy; metformin and sulfonylurea combination; metformin and other antihyperglycemic medications; all other combinations of oral antihyperglycemic medications. Survival was calculated from the date of cancer diagnosis to the date of death or the end of follow-up (31 December 2018). Results: Study group included 454 diabetic patients with pancreatic cancer. We found no statistically significant differences in overall survival between patients by glucose-lowering therapy. However, highest mortality risk was observed in patients on insulin monotherapy, and better survival was observed in the groups of patients using antihyperglycemic medication combinations, metformin alone, and metformin in combination with sulfonylurea. Analysis by cumulative dose of metformin showed significantly lower mortality risk in the highest cumulative dose category (HR 0.76, 95% CI 0.58–0.99). Conclusions: Our study showed that metformin might have a survival benefit for pancreatic cancer patients, suggesting a potentially available option for the treatment.
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Affiliation(s)
- Audrius Dulskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania;
- Correspondence: ; Tel.: +37-067-520-094
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406 Vilnius, Lithuania; (A.P.); (G.S.)
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania
| | | | - Lina Zabuliene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania;
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406 Vilnius, Lithuania; (A.P.); (G.S.)
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania
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Srivastava SP, Goodwin JE. Cancer Biology and Prevention in Diabetes. Cells 2020; 9:cells9061380. [PMID: 32498358 PMCID: PMC7349292 DOI: 10.3390/cells9061380] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
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Kirtonia A, Gala K, Fernandes SG, Pandya G, Pandey AK, Sethi G, Khattar E, Garg M. Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics. Semin Cancer Biol 2020; 68:258-278. [PMID: 32380233 DOI: 10.1016/j.semcancer.2020.04.006] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023]
Abstract
Human malignancies are one of the major health-related issues though out the world and anticipated to rise in the future. The development of novel drugs/agents requires a huge amount of cost and time that represents a major challenge for drug discovery. In the last three decades, the number of FDA approved drugs has dropped down and this led to increasing interest in drug reposition or repurposing. The present review focuses on recent concepts and therapeutic opportunities for the utilization of antidiabetics, antibiotics, antifungal, anti-inflammatory, antipsychotic, PDE inhibitors and estrogen receptor antagonist, Antabuse, antiparasitic and cardiovascular agents/drugs as an alternative approach against human malignancies. The repurposing of approved non-cancerous drugs is an effective strategy to develop new therapeutic options for the treatment of cancer patients at an affordable cost in clinics. In the current scenario, most of the countries throughout the globe are unable to meet the medical needs of cancer patients because of the high cost of the available cancerous drugs. Some of these drugs displayed potential anti-cancer activity in preclinic and clinical studies by regulating several key molecular mechanisms and oncogenic pathways in human malignancies. The emerging pieces of evidence indicate that repurposing of drugs is crucial to the faster and cheaper discovery of anti-cancerous drugs.
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Affiliation(s)
- Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India; Equal contribution
| | - Kavita Gala
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India; Equal contribution
| | - Stina George Fernandes
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India; Equal contribution
| | - Gouri Pandya
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India; Equal contribution
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana, 122413, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Ekta Khattar
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be University), Vile Parle West, Mumbai, 400056, India.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India.
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Usman S, Khawer M, Rafique S, Naz Z, Saleem K. The current status of anti-GPCR drugs against different cancers. J Pharm Anal 2020; 10:517-521. [PMID: 33425448 PMCID: PMC7775845 DOI: 10.1016/j.jpha.2020.01.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 01/06/2020] [Accepted: 01/10/2020] [Indexed: 12/23/2022] Open
Abstract
G protein coupled receptors (GPCRs) have emerged as the most potential target for a number of drug discovery programs ranging from control of blood pressure, diabetes, cure for genetic diseases to treatment of cancer. A panel of different ligands including hormones, peptides, ions and small molecules is responsible for activation of these receptors. Molecular genetics has identified key GPCRs, whose mutations or altered expressions are linked with tumorgenicity. In this review, we discussed recent advances regarding the involvement of GPCRs in the development of cancers and approaches to manipulating the mechanism behind GPCRs involved tumor growth and metastasis to treat different types of human cancer. This review provides an insight into the current scenario of GPCR-targeted therapy, progress to date and the challenges in the development of anticancer drugs.
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Affiliation(s)
- Sana Usman
- Centre for Applied Molecular Biology, 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Maria Khawer
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Shazia Rafique
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Zara Naz
- Centre for Applied Molecular Biology, 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Komal Saleem
- Centre for Applied Molecular Biology, 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
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Abstract
Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its outstanding ability to decrease plasma glucose levels. Over time, different uses of metformin were discovered, and the benefits of metformin for various diseases and even aging were verified. These diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, liver diseases, cardiovascular disease, and renal diseases. Metformin exerts different effects through different signaling pathways. However, the underlying mechanisms of these different benefits remain to be elucidated. The aim of this review is to provide a brief summary of the benefits of metformin and to discuss the possible underlying mechanisms.
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Affiliation(s)
- Ziquan Lv
- Department of Molecular Epidemiology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yajie Guo
- The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yajie Guo
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Kim HS, Kim JH, Jang HJ, Lee J. The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials. Int J Med Sci 2020; 17:2551-2560. [PMID: 33029097 PMCID: PMC7532491 DOI: 10.7150/ijms.50338] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/01/2020] [Indexed: 12/14/2022] Open
Abstract
Preclinical studies have demonstrated that metformin has anticancer properties and act in additive or synergistic way when combined with anticancer agents. We conducted this meta-analysis of randomized clinical trials to evaluate the effect of metformin added to systemic anticancer therapy in patients with advanced or metastatic cancer. A computerized systematic electronic search was performed using PubMed, PMC, EMBASE, Cochrane Library, and Web of Science databases (up to June 2020). From nine randomized clinical trials, 821 patients were included in the pooled analyses of odds ratios (ORs) with 95% confidence intervals (CIs) for overall response rate (ORR) and hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). The concomitant use of metformin with systemic anticancer therapy did not increase tumor response (the pooled OR of ORR = 1.23, 95% CI: 0.89-1.71, p = 0.21), compared with anticancer therapy alone. In terms of survival, metformin added to anticancer agents failed to prolong PFS (HR = 0.95, 95% CI: 0.75-1.21, p = 0.68) and OS (HR = 0.97, 95% CI: 0.80-1.16, p = 0.71). In conclusion, this meta-analysis of randomized clinical trials indicates that the addition of metformin to systemic anticancer therapy has no clinical benefits in patients with advanced or metastatic cancer.
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Affiliation(s)
- Hyeong Su Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung 18450, Gyeonggi-Do, Republic of Korea
| | - Jin Lee
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung 18450, Gyeonggi-Do, Republic of Korea
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Sun Y, Chen X, Zhou Y, Qiu S, Wu Y, Xie M, Zhu G, Liang S, Li H, Zhou D, Ju Z, Wang F, Han F, Wang Z, Wang R. Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation. Int J Med Sci 2020; 17:2416-2426. [PMID: 33029084 PMCID: PMC7532475 DOI: 10.7150/ijms.48635] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 08/04/2020] [Indexed: 12/23/2022] Open
Abstract
Objective: To explore a way to reverse the drug resistance for irradiated CNE-1 human nasopharyngeal carcinoma cells and try to develop a new high efficacy with low toxicity therapeutic approach. Methods: 300 Gy irradiated the CNE-1 human nasopharyngeal carcinoma cells, and then treated with single-agent cisplatin or metformin, or combination of both drugs. MTT assay and FCM were applied to detect cell viability and apoptosis. Western blot and RT-PCR were used to characterize the protein and mRNA expression after various drug administrations. Results: The results presented single-agent metformin was capable of arresting the tumor growth and inducing apoptosis in irradiated CNE-1 cells and also demonstrated a synergy effect with cisplatin. Furthermore, metformin down-regulates the PECAM-1 expression, which could regulate Multi-drug Resistance-associate Proteins (MRPs) expression leading to cisplatin resistance of irradiated CNE-1 cells. A pan-MRP inhibitor, probenecid, can resecure cisplatin resistance leading by radiation. Conclusions: Metformin, due to its independent effects on PECAM-1, had a unique anti-proliferative effect on irradiated CNE-1 cells. It would be a new therapeutic option to conquer cisplatin resistance for advanced NPC patients after radiotherapy.
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Affiliation(s)
- Yingming Sun
- Department of Medical and Radiation Oncology, Sanming First Hospital of Fujian Medical University. Sanming 365001, China.,Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China
| | - Xiaochuan Chen
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350001, China
| | - Yajuan Zhou
- Department of Radiotherapy, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology. Wuhan, 430074, China
| | - Sufang Qiu
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350001, China
| | - Yongyang Wu
- Department of Urology Surgery, Sanming First Hospital of Fujian Medical University. Sanming 365001, China
| | - Min Xie
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China
| | - Guofang Zhu
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China
| | - Shanshan Liang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Heming Li
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Dong Zhou
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Zaishuang Ju
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Fuguang Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Fang Han
- Department of Medical Imaging, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China
| | - Zhe Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
| | - Ruoyu Wang
- Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China
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Immune-mediated anti-tumor effects of metformin; targeting metabolic reprogramming of T cells as a new possible mechanism for anti-cancer effects of metformin. Biochem Pharmacol 2019; 174:113787. [PMID: 31884044 DOI: 10.1016/j.bcp.2019.113787] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/24/2019] [Indexed: 12/11/2022]
Abstract
Immunotherapy-based cancer treatment has revolutionized the era of cancer patients recuperation and it has brought a strong hope to treatment of some types of cancers. Metformin, a widely used antidiabetic drug, which has intensely been studied for its anticancer effects, is believed to have positive influences on immune responses against tumor cells. Metformin can affect metabolic pathways within cells mainly through activation of AMPK. Metabolic restriction of tumor microenvironment on effector immune cells is one of the important strategies favoring tumor cells to escape from immunogenic cell death. The metabolism of T cells has an axial role in shaping and supporting immune responses and may have an important role in anticancer immunity, suggesting that the functionality and durability of tumor-specific T cells need sufficient energy and nutrients. Energy biogenesis of tumor-specific cytotoxic T cells has become an interesting field of study and it is suggested that activation and maintenance of effector T cell responses in tumor microenvironment may occur by metabolic reprogramming of T cells. AMPK has been noticed as the main intracellular energy sensor and mitochondrial biogenesis key regulator which can control and regulate metabolic reprogramming in immune cells and increase antitumor immunity. Metabolic reprogramming of T cells to overcome metabolic restriction in tumor microenvironment, maiming effector T cell responses against tumor cells, has been noticed by several studies. Here we represent metformin, an AMPK activator, as a new candidate drug for metabolic reprogramming of tumor-specific T cells to increase the efficacy and accountability of cancer immunotherapy.
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Dong TS, Chang HH, Hauer M, Lagishetty V, Katzka W, Rozengurt E, Jacobs JP, Eibl G. Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity. Am J Physiol Gastrointest Liver Physiol 2019; 317:G763-G772. [PMID: 31545922 PMCID: PMC6962494 DOI: 10.1152/ajpgi.00170.2019] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 09/11/2019] [Accepted: 09/15/2019] [Indexed: 01/31/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.
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Affiliation(s)
- Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Hui-Hua Chang
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Meg Hauer
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Venu Lagishetty
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - William Katzka
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Enrique Rozengurt
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Jonathan P Jacobs
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Guido Eibl
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, California
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Toriola AT, Luo S, Thomas TS, Drake BF, Chang SH, Sanfilippo KM, Carson KR. Metformin Use and Pancreatic Cancer Survival among Non-Hispanic White and African American U.S. Veterans with Diabetes Mellitus. Cancer Epidemiol Biomarkers Prev 2019; 29:169-175. [DOI: 10.1158/1055-9965.epi-19-0781] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/26/2019] [Accepted: 10/29/2019] [Indexed: 11/16/2022] Open
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Gupta MK, Vasudevan NT. GPCRs and Insulin Receptor Signaling in Conversation: Novel Avenues for Drug Discovery. Curr Top Med Chem 2019; 19:1436-1444. [PMID: 31512997 DOI: 10.2174/1568026619666190712211642] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/17/2019] [Accepted: 01/24/2019] [Indexed: 01/02/2023]
Abstract
Type 2 diabetes is a major health issue worldwide with complex metabolic and endocrine abnormalities. Hyperglycemia, defects in insulin secretion and insulin resistance are classic features of type 2 diabetes. Insulin signaling regulates metabolic homeostasis by regulating glucose and lipid turnover in the liver, skeletal muscle and adipose tissue. Major treatment modalities for diabetes include the drugs from the class of sulfonyl urea, Insulin, GLP-1 agonists, SGLT2 inhibitors, DPP-IV inhibitors and Thiazolidinediones. Emerging antidiabetic therapeutics also include classes of drugs targeting GPCRs in the liver, adipose tissue and skeletal muscle. Interestingly, recent research highlights several shared intermediates between insulin and GPCR signaling cascades opening potential novel avenues for diabetic drug discovery.
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Affiliation(s)
- Manveen K Gupta
- Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio 44106, United States
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Li Y, Bian X, Wei S, He M, Yang Y. The relationship between pancreatic cancer and type 2 diabetes: cause and consequence. Cancer Manag Res 2019; 11:8257-8268. [PMID: 31571983 PMCID: PMC6750859 DOI: 10.2147/cmar.s211972] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/23/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is a devastating and lethal malignant disease and it is well known that there is a complex bidirectional relationship between PC and type 2 diabetes mellitus (T2DM). In order to more deeply summarize the relationship between them, this article summarizes the epidemiological data on the relationship between PC and T2DM in the past 5 years, and further explains the mechanism of interaction between them. Meanwhile, it also summed up the effects of drug therapy for T2DM on PC and the impact of T2DM on surgical resection of PC. Epidemiological studies clearly indicate that the risk of PC is increased in patients with T2DM. But increasing epidemiological data points out that PC also acts as a cause of T2DM and new-onset T2DM is sign and consequence of PC. Insulin resistance, hyperinsulinemia, hyperglycemia, and chronic inflammation are the mechanisms of T2DM-Associated PC. Metformin decreases the risk of PC, while insulin therapy increases the risk of PC. Besides, studies have shown that T2DM decreases the survival in patients with PC resection.
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Affiliation(s)
- Yan Li
- Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Xiaohui Bian
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Shuyi Wei
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Meizhi He
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yuelian Yang
- Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
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A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through Mitochondrial Disintegration and Metabolic Collapse. Int J Mol Sci 2019; 20:ijms20174208. [PMID: 31466233 PMCID: PMC6747461 DOI: 10.3390/ijms20174208] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/22/2019] [Accepted: 08/23/2019] [Indexed: 01/08/2023] Open
Abstract
Cancer cells preferentially utilize glycolysis for ATP production even in aerobic conditions (the Warburg effect) and adapt mitochondrial processes to their specific needs. Recent studies indicate that altered mitochondrial activities in cancer represent an actionable target for therapy. We previously showed that salt 1-3C, a quinoxaline unit (with cytotoxic activity) incorporated into a meso-substituted pentamethinium salt (with mitochondrial selectivity and fluorescence properties), displayed potent cytotoxic effects in vitro and in vivo, without significant toxic effects to normal tissues. Here, we investigated the cytotoxic mechanism of salt 1-3C compared to its analogue, salt 1-8C, with an extended side carbon chain. Live cell imaging demonstrated that salt 1-3C, but not 1-8C, is rapidly incorporated into mitochondria, correlating with increased cytotoxicity of salt 1-3C. The accumulation in mitochondria led to their fragmentation and loss of function, accompanied by increased autophagy/mitophagy. Salt 1-3C preferentially activated AMP-activated kinase and inhibited mammalian target of rapamycin (mTOR) signaling pathways, sensors of cellular metabolism, but did not induce apoptosis. These data indicate that salt 1-3C cytotoxicity involves mitochondrial perturbation and disintegration, and such compounds are promising candidates for targeting mitochondria as a weak spot of cancer.
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Li L, Jiang L, Wang Y, Zhao Y, Zhang XJ, Wu G, Zhou X, Sun J, Bai J, Ren B, Tian K, Xu Z, Xiao HL, Zhou Q, Han R, Chen H, Wang H, Yang Z, Gao C, Cai S, He Y. Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: A Randomized, Double-Blind Phase II Trial. Clin Cancer Res 2019; 25:6967-6975. [PMID: 31413010 DOI: 10.1158/1078-0432.ccr-19-0437] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 06/13/2019] [Accepted: 08/09/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm). PATIENTS AND METHODS A total of 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis. RESULTS The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2% [95% confidence interval (CI), 30.0-52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6-52.7) with gefitinib plus placebo (P = 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%). CONCLUSIONS Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC.
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Affiliation(s)
- Li Li
- Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Liyan Jiang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yubo Wang
- Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yizhuo Zhao
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Ju Zhang
- Department of Pulmonary Medicine, People's Hospital of Henan Province, Zhengzhou, China
| | - Guoming Wu
- Department of Respiratory Medicine and Respiratory Intensive Care Unit, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiangdong Zhou
- Department of Respiratory Medicine, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jianguo Sun
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jun Bai
- Department of Medical Oncology, People's Hospital of Shanxi Province, Xi'an, China
| | - Biyong Ren
- Cancer Center, Chongqing Three Gorges Central Hospital, Chongqing, China
| | - Kun Tian
- Department of Respiratory Medicine, General Hospital of Chengdu Military Region of PLA, Chengdu, China
| | - Zhi Xu
- Department of Respiratory Medicine and Respiratory Intensive Care Unit, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hua-Liang Xiao
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing, China
| | - Qi Zhou
- Department of Oncology, Fuling Center Hospital, Chongqing, China
| | - Rui Han
- Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Hengyi Chen
- Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Haidong Wang
- Department of Thoracic Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zhenzhou Yang
- Department of Oncology, Daping Hospital, Army Medical University, Chongqing, China
| | - Chan Gao
- The Medical Department, 3D Medicines Inc., Shanghai, P.R. China
| | - Shangli Cai
- The Medical Department, 3D Medicines Inc., Shanghai, P.R. China
| | - Yong He
- Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China.
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49
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Hu G, He M, Ko WKW, Ye C, Hu Q, Wong AOL. IGFs Potentiate TAC3-induced SLα Expression via Upregulation of TACR3 Expression in Grass Carp Pituitary Cells. Cells 2019; 8:cells8080887. [PMID: 31412674 PMCID: PMC6721824 DOI: 10.3390/cells8080887] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/06/2019] [Accepted: 08/10/2019] [Indexed: 12/28/2022] Open
Abstract
In mammals, the tachykinin 3 (TAC3)/tachykinin receptor 3 (TACR3) systems have been confirmed to play an important role in the regulation of puberty onset. Using grass carp pituitary cells as the model, our recent study found that the TAC3 gene products could significantly induce somatolactin α (SLα) synthesis and secretion via TACR3 activation. In the present study, we seek to examine if pituitary TACR3 can serve as a regulatory target and contribute to TAC3 interactions with other SLα regulators. Firstly, grass carp TACR3 was cloned and tissue distribution showed that it could be highly detected in grass carp pituitary. Using HEK293 cells as the model, functional expression also revealed that grass carp TACR3 exhibited ligand binding selectivity and post-receptor signaling highly comparable to its mammalian counterpart. Using grass carp pituitary cells as the model, TACR3 mRNA expression could be stimulated by insulin-like growth factor (IGF)-I and -II via the IGF-I receptor coupled to phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. Interestingly, IGF-I/-II cotreatment could also significantly enhance TAC3-induced SLα mRNA expression and the potentiating effect was dependent on TACR3 expression and activation of adenylate cyclase (AC)/cAMP/protein kinase A (PKA), phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3)/protein kinase C (PKC), and Ca2+/calmodulin (CaM)/calmodulin-dependent protein kinase II (CaMK-II) cascades. Besides, IGF-I-induced Akt phosphorylation but not MEK, extracellular signal-regulated kinase (ERK1/2), and P38MAPK phosphorylation was notably enhanced by TACR3 activation. These results, as a whole, suggest that the potentiating effect of IGFs on TAC3 gene products-induced SLα mRNA expression was mediated by TACR3 upregulation and functional crosstalk of post-receptor signaling in the pituitary.
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Affiliation(s)
- Guangfu Hu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
| | - Mulan He
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Wendy K W Ko
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Cheng Ye
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Qiongyao Hu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China
| | - Anderson O L Wong
- School of Biological Sciences, University of Hong Kong, Hong Kong, China.
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50
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Wang JC, Li GY, Wang B, Han SX, Sun X, Jiang YN, Shen YW, Zhou C, Feng J, Lu SY, Liu JL, Wang MD, Liu PJ. Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:235. [PMID: 31164151 PMCID: PMC6549289 DOI: 10.1186/s13046-019-1211-2] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/03/2019] [Indexed: 12/29/2022]
Abstract
Background Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis. Methods Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin’s vascular effects. Results Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, “vessel normalization”. Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin’s vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization. Conclusions These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1211-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ji-Chang Wang
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.,Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China
| | - Guang-Yue Li
- Department of Science and Technology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Bo Wang
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China
| | - Su-Xia Han
- Department of Oncological Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Xin Sun
- Department of Thoracic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yi-Na Jiang
- Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Yan-Wei Shen
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Can Zhou
- Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jun Feng
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Shao-Ying Lu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jian-Lin Liu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Mao-De Wang
- Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China.
| | - Pei-Jun Liu
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China. .,Key Laboratory for Tumor Precision Medicine of Shaanxi Province, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China.
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