|
1
|
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.
Collapse
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.
| |
Collapse
|
|
2
|
Pradhan PM, Lee YH, Jang S, Yi HK. Synergistic anti-cancer effects of metformin and cisplatin on YD-9 oral squamous carcinoma cells via AMPK pathway. J Appl Oral Sci 2025; 33:e20240385. [PMID: 40008711 DOI: 10.1590/1678-7757-2024-0385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 01/07/2025] [Indexed: 02/27/2025] Open
Abstract
OBJECTIVE This study evaluated whether hypoglycemic drug metformin enhances the anti-cancer effects of cisplatin in YD-9 cells. METHODOLOGY YD-9 cells, derived from oral mucosal squamous cell carcinoma of oral mucosa, were used to assess the combined effects of metformin and cisplatin by means of MTT assay, live and dead cell staining, and colony formation assays to evaluate cell viability and proliferation. Reactive oxygen species level was measured using a Muse cell analyzer. Apoptosis, epithelial-mesenchymal transition, and related molecular pathways were analyzed by western blot. Wound healing assays and Transwell migration assays examined cell migration, whereas monophosphate-activated protein kinase inhibitor Compound C, was utilized to investigate the AMPK pathway. RESULTS Sequential treatment of YD-9 cells with metformin and cisplatin resulted in decreased cell viability and proliferation, increased ROS levels, and elevated apoptosis compared with the individual drugs. Moreover, the treatment inhibited EMT, wound healing, and cell migration. These results correlated with increased AMPK phosphorylation, a key regulator of cellular energy homeostasis. Introduction of Compound C pre-treatment upregulated N-cadherin and α-smooth muscle actin along with enhanced cell migration. CONCLUSION This study found synergism in anti-cancer effects between metformin and cisplatin. Additionally, introduction of Compound C confirmed that EMT inhibition is AMPK dependent. These findings indicate the potential use of metformin as an adjunct drug in anti-cancer treatments, warranting further investigation.
Collapse
Affiliation(s)
- Paras Man Pradhan
- Jeonbuk National University, Institute of Oral Bioscience, School of Dentistry, Department of Oral Biochemistry, Jeonju, Korea
| | - Young-Hee Lee
- Jeonbuk National University, Institute of Oral Bioscience, School of Dentistry, Department of Oral Biochemistry, Jeonju, Korea
| | - Sungil Jang
- Jeonbuk National University, Institute of Oral Bioscience, School of Dentistry, Department of Oral Biochemistry, Jeonju, Korea
| | - Ho-Keun Yi
- Jeonbuk National University, Institute of Oral Bioscience, School of Dentistry, Department of Oral Biochemistry, Jeonju, Korea
| |
Collapse
|
|
3
|
Shabkhizan R, Avci ÇB, Haiaty S, Moslehian MS, Sadeghsoltani F, Bazmani A, Mahdipour M, Takanlou LS, Takanlou MS, Zamani ARN, Rahbarghazi R. Metformin exerted tumoricidal effects on colon cancer tumoroids via the regulation of autophagy pathway. Stem Cell Res Ther 2025; 16:45. [PMID: 39901295 PMCID: PMC11792360 DOI: 10.1186/s13287-025-04174-z] [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: 05/20/2024] [Accepted: 01/23/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Despite the existence of promising outcomes from standard 2D culture systems, these data are not completely akin to in vivo tumor parenchyma. Therefore, the development and fabrication of various 3D culture systems can in part mimic intricate cell-to-cell interaction within the real tumor mass. Here, we aimed to evaluate the tumoricidal impacts of metformin (MTF) on colorectal cancer (CRC) tumoroids in an in vitro system via the modulation of autophagy. METHODS CRC tumoroids were developed using human umbilical vein endothelial cells (HUVECs), adenocarcinoma HT29 cells, and fibroblasts (HFFF2) in a ratio of 1: 2: 1 and 2.5% methylcellulose. Tumoroids were exposed to different concentrations of MTF, ranging from 20 to 1000 mM, for 72 h. The survival rate was detected using an LDH release assay. The expression and protein levels of autophagy-related factors were measured using PCR array and western blotting, respectively. Using H & E, and immunofluorescence staining (Ki-67), the integrity and proliferation rate of CRC tumoroids were examined. RESULTS The current protocol yielded typical compact tumoroids with a dark central region. Despite slight changes in released LDH contents, no statistically significant differences were achieved in terms of cell toxicity in MTF-exposed groups compared to the control tumoroids, indicating the insufficiency of MTF in the induction of tumor cell death (p > 0.05). Western blotting indicated that the LC3II/I ratio was reduced in tumoroids exposed to 120 mM MTF (p < 0.05). These data coincided with the reduction of intracellular p62 content in MTF 120 mM-treated tumoroids compared to MTF 40 mM and control groups (p < 0.05). PCR array analysis confirmed the up-regulation, and down-regulation of several genes related to various signaling transduction pathways associated with autophagy machinery and shared effectors between autophagy and apoptosis in 40 and 120 mM MTF groups compared to the non-treated control group (p < 0.05). These changes were more prominent in tumoroids incubated with 120 mM MTF. Histological examination confirmed the loosening integrity of tumoroids in MTF-treated groups, especially 120 mM MTF, with the increase in cell death via the induction of apoptosis (chromatin marginalization) and necrotic (pyknotic nuclei) changes. In the 120 mM MTF group, spindle-shaped cells with the remnants of a fibrillar matrix were detected. Data indicated the reduction of proliferating Ki-67+ cells within the tumoroids by increasing the MTF concentration from 40 to 120 mM. CONCLUSIONS Different shared autophagy/apoptosis genes were modulated in CRC tumoroids after MTF treatment coinciding with both typical necrotic and apoptotic cells within the tumoroid structure. MTF can inhibit the integrity and proliferation of CRC tumoroids in dose-dependent manner.
Collapse
Affiliation(s)
- Roya Shabkhizan
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Çığır Biray Avci
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Sanya Haiaty
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziyeh Sadat Moslehian
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Bazmani
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | | | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
4
|
Jordan E, Arriaga MA, Obregon H, Villalobos V, Duarte MA, Garcia K, Levy A, Chew SA. Dual delivery of metformin and Y15 from a PLGA scaffold for the treatment of platinum-resistant ovarian cancer. Future Med Chem 2025; 17:301-312. [PMID: 39887289 PMCID: PMC11792864 DOI: 10.1080/17568919.2025.2458457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025] Open
Abstract
AIMS Drug-loaded poly(lactic-co-glycolic acid) (PLGA) scaffolds were fabricated using a mold-less technique to investigate whether the combined delivery of both Y15 (FAK inhibitor) and metformin would result in enhanced effects on cell viability compared to the release of each drug alone for the treatment of platinum-resistant ovarian cancer (PROC). MATERIALS & METHODS Scaffolds were fabricated using an easy and economical mold-less technique that combined PLGA and the drugs (i.e. metformin and/or Y15) in tetraglycol and injected in PBS, to form a globular morphology. RESULTS The exposure of cells to metformin and Y15 resulted in a significantly enhanced cytotoxic efficacy compared to single-drug treatment with either metformin or Y15. When the drugs were delivered using the PLGA scaffolds, the combination of the two drugs was significantly more cytotoxic compared to scaffolds containing metformin only and Y15 only. CONCLUSIONS The combination of metformin and Y15 can result in an increase in antitumor activity in PROC cells through apoptosis. The delivery of both drugs from the PLGA biomaterial scaffold allowed for a more enhanced combinational effect compared to the utilization of free drugs (without a scaffold) and should be further explored as a promising treatment of PROC.
Collapse
Affiliation(s)
- Emily Jordan
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Marco A. Arriaga
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Hannah Obregon
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Viviana Villalobos
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Manuel A. Duarte
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Kristal Garcia
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Arkene Levy
- Dr Kiran C Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Sue Anne Chew
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| |
Collapse
|
|
5
|
Zhang Y, Wu Y, Liu Z, Yang K, Lin H, Xiong K. Non-coding RNAs as potential targets in metformin therapy for cancer. Cancer Cell Int 2024; 24:333. [PMID: 39354464 PMCID: PMC11445969 DOI: 10.1186/s12935-024-03516-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 09/24/2024] [Indexed: 10/03/2024] Open
Abstract
Metformin, a widely used oral hypoglycemic drug, has emerged as a potential therapeutic agent for cancer treatment. While initially known for its role in managing diabetes, accumulating evidence suggests that metformin exhibits anticancer properties through various mechanisms. Several cellular or animal experiments have attempted to elucidate the role of non-coding RNA molecules, including microRNAs and long non-coding RNAs, in mediating the anticancer effects of metformin. The present review summarized the current understanding of the mechanisms by which non-coding RNAs modulate the response to metformin in cancer cells. The regulatory roles of non-coding RNAs, particularly miRNAs, in key cellular processes such as cell proliferation, cell death, angiogenesis, metabolism and epigenetics, and how metformin affects these processes are discussed. This review also highlights the role of lncRNAs in cancer types such as lung adenocarcinoma, breast cancer, and renal cancer, and points out the need for further exploration of the mechanisms by which metformin regulates lncRNAs. In addition, the present review explores the potential advantages of metformin-based therapies over direct delivery of ncRNAs, and this review highlights the mechanisms of non-coding RNA regulation when metformin is combined with other therapies. Overall, the present review provides insights into the molecular mechanisms underlying the anticancer effects of metformin mediated by non-coding RNAs, offering novel opportunities for the development of personalized treatment strategies in cancer patients.
Collapse
Affiliation(s)
- Yihan Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang, China
| | - Yunhao Wu
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang, China
| | - Zixu Liu
- The First School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Kangping Yang
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang, China
| | - Kai Xiong
- Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China.
| |
Collapse
|
|
6
|
Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [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: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
Collapse
Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| |
Collapse
|
|
7
|
Wu Z, Wang W, Wei L, Zhu S. Current status and frontier tracking of clinical trials on Metformin for cancer treatment. J Cancer Res Clin Oncol 2023; 149:16931-16946. [PMID: 37698682 DOI: 10.1007/s00432-023-05391-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 09/01/2023] [Indexed: 09/13/2023]
Abstract
PURPOSE Metformin has been used clinically for more than six decades. Over time, numerous remarkable effects of metformin beyond the clinic have been discovered and discussed. Metformin has been shown to have a favorable impact on cancer therapy in addition to its clinically recognized hypoglycemic effect. However, the antitumor efficacy of metformin in humans has not been clearly demonstrated yet. Hence, a systematic analysis of the existing trials is necessary. METHODS Here, we retrieved clinical trials from the Clinical Trials.gov database to overview the clinical development of metformin for the treatment of cancer, analyze existing clinical results, and summarize some promising applications for specific cancer therapies. RESULTS The potential application of metformin contains three directions: Firstly, improvement of metabolic factors associated with treatment effects, such as insulin resistance and peripheral neuropathy. Secondly, in combination with immune checkpoint blockade effects. Finally, use it for the endocrine treatment of hormone-dependent cancers. CONCLUSION Although the outcomes of metformin as a repurposed agent in some trials have been unsatisfactory, it still has the potential to be used in select cancer therapy settings.
Collapse
Affiliation(s)
- Zhipeng Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Wei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lengyun Wei
- School of Life Science, Anhui Medical University, Hefei, China.
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.
| |
Collapse
|
|
8
|
Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
Collapse
Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| |
Collapse
|
|
9
|
Buckley CE, O’Brien RM, Nugent TS, Donlon NE, O’Connell F, Reynolds JV, Hafeez A, O’Ríordáin DS, Hannon RA, Neary P, Kalbassi R, Mehigan BJ, McCormick PH, Dunne C, Kelly ME, Larkin JO, O’Sullivan J, Lynam-Lennon N. Metformin is a metabolic modulator and radiosensitiser in rectal cancer. Front Oncol 2023; 13:1216911. [PMID: 37601689 PMCID: PMC10435980 DOI: 10.3389/fonc.2023.1216911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.
Collapse
Affiliation(s)
- Croí E. Buckley
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Rebecca M. O’Brien
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Timothy S. Nugent
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | - Noel E. Donlon
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Department of Surgery, Beacon Hospital, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Fiona O’Connell
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - John V. Reynolds
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Adnan Hafeez
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | | | | | - Paul Neary
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | - Reza Kalbassi
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | - Brian J. Mehigan
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Paul H. McCormick
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Cara Dunne
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Michael E. Kelly
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - John O. Larkin
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
10
|
Zhuang Y, Haugrud AB, Schaefer MA, Messerli SM, Miskimins WK. Ability of metformin to deplete NAD+ contributes to cancer cell susceptibility to metformin cytotoxicity and is dependent on NAMPT expression. Front Oncol 2023; 13:1225220. [PMID: 37583931 PMCID: PMC10424729 DOI: 10.3389/fonc.2023.1225220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/07/2023] [Indexed: 08/17/2023] Open
Abstract
Background Nicotinamide adenine dinucleotide (NAD+) is vital for not only energy metabolism but also signaling pathways. A major source of NAD+ depletion is the activation of poly (ADP-ribose) polymerase (PARP) in response to DNA damage. We have previously demonstrated that metformin can cause both caspase-dependent cell death and PARP-dependent cell death in the MCF7 breast cancer cells but not in the MDA-MB-231 (231) breast cancer cells while in high-glucose media. We hypothesize that depletion of NAD+ in MCF7 cells via activation of PARP contributes to the cell death caused by metformin. Nicotinamide phosphoribosyltransferase (NAMPT), a key rate-limiting step in converting nicotinamide (vitamin B3) into NAD+, is essential for regenerating NAD+ for normal cellular processes. Evidence shows that overexpression of NAMPT is associated with tumorigenesis. We hypothesize that NAMPT expression may determine the extent to which cancer cells are sensitive to metformin. Results In this study, we found that metformin significantly decreases NAD+ levels over time, and that this could be delayed by PARP inhibitors. Pretreatment with NAD+ in MCF7 cells also prevents cell death and the enlargement of mitochondria and protects mitochondria from losing membrane potential caused by metformin. This leads to MCF7 cell resistance to metformin cytotoxicity in a manner similar to 231 cells. By studying the differences in NAD+ regulation in these two breast cancer cell lines, we demonstrate that NAMPT is expressed at higher levels in 231 cells than in MCF7 cells. When NAMPT is genetically repressed in 231 cells, they become much more sensitive to metformin-induced cell death. Conversely, overexpressing NAMPT in HEK-293 (293) cells causes the cells to be more resistant to metformin's growth inhibitory effects. The addition of a NAMPT activator also decreased the sensitivity of MCF7 cells to metformin, while the NAMPT activator, P7C3, protects against metformin-induced cytotoxicity. Conclusions Depletion of cellular NAD+ is a key aspect of sensitivity of cancer cells to the cytotoxic effects of metformin. NAMPT plays a key role in maintaining sufficient levels of NAD+, and cells that express elevated levels of NAMPT are resistant to killing by metformin.
Collapse
Affiliation(s)
- Yongxian Zhuang
- Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, United States
| | - Allison B. Haugrud
- Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, United States
| | - Meg A. Schaefer
- Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, United States
- Sanford Program for Undergraduate Research (SPUR) Program, Sanford Research, Sioux Falls, SD, United States
| | - Shanta M. Messerli
- Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, United States
| | - W. Keith Miskimins
- Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, United States
| |
Collapse
|
|
11
|
Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther 2023; 17:1907-1932. [PMID: 37397787 PMCID: PMC10312383 DOI: 10.2147/dddt.s409373] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/10/2023] [Indexed: 07/04/2023] Open
Abstract
Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.
Collapse
Affiliation(s)
- Siddhartha Dutta
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Rima B Shah
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Shubha Singhal
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Sudeshna Banerjee Dutta
- Department of Medical Surgical Nursing, Shri Anand Institute of Nursing, Rajkot, Gujarat, 360005, India
| | - Sumit Bansal
- Department of Anaesthesiology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Susmita Sinha
- Department of Physiology, Khulna City Medical College and Hospital, Khulna, Bangladesh
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, 57000, Malaysia
| |
Collapse
|
|
12
|
Rosidi B, Priyatno D, Putra TP, Yusuf I. Metformin Induces a Caspase 3-Unrelated Apoptosis in Human Colorectal Cancer Cell Lines HCT116 and SW620. Cancer Manag Res 2023; 15:475-485. [PMID: 37312884 PMCID: PMC10259592 DOI: 10.2147/cmar.s385278] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 03/16/2023] [Indexed: 06/15/2023] Open
Abstract
Purpose To study the effects of metformin on the proliferation and growth of human colorectal cancer cell lines HCT116 and SW620. Materials and Methods The antiproliferative effect of metformin was assayed using an MTS reagent and its ability to inhibit colony formation was demonstrated using a clonogenic assay. Flow cytometry using YO-PRO-1/PI was performed to examine the effects of metformin on apoptosis and cell death of HCT116 and SW620. Caspase 3 activities were measured in caspase-3 activity tests using a caspase-3 activity kit. Furthermore, Western blots were performed with anti-PARP1, anti-caspase 3, and anti-cleaved caspase 3 to confirm whether caspase activation was present or not. Results Both MTS proliferation assays and clonogenic assays showed that metformin inhibited the proliferation and growth of HCT116 and SW620 cells in a concentration-dependent manner. Flow cytometric analysis identified early apoptosis and metformin-induced cell death in both cell lines. However, caspase 3 activity could not be detected. Cleavage of both PARP1 and pro-caspase 3 was not observed in the Western blot, confirming the absence of caspase 3 activations. Conclusion This present study suggests a caspase 3-unrelated apoptosis mechanism of metformin-induced cell death in human colorectal cancer cell lines HCT116 and SW620.
Collapse
Affiliation(s)
- Bustanur Rosidi
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Diana Priyatno
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Teguh Pribadi Putra
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
| | - Irawan Yusuf
- Division of Proteomics, Mochtar Riady Institute for Nanotechnology and Medical Science Group, University of Pelita Harapan, Tangerang, Banten, Indonesia
- Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| |
Collapse
|
|
13
|
Lange C, Brüggemann J, Thüner T, Jauckus J, Strowitzki T, Germeyer A. Changes in the expression of cancer- and metastasis-related genes and proteins after metformin treatment under different metabolic conditions in endometrial cancer cells. Heliyon 2023; 9:e16678. [PMID: 37313172 PMCID: PMC10258389 DOI: 10.1016/j.heliyon.2023.e16678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 05/20/2023] [Accepted: 05/24/2023] [Indexed: 06/15/2023] Open
Abstract
Research question Hyperinsulinemia and elevated estrogen levels are known risk factors for endometrial cancer (EC) development and are associated with obesity, type 2 diabetes mellitus (T2DM), insulin resistance, among others. Metformin, an insulin-sensitizing drug, displays anti-tumor effects in cancer patients, including EC, but the mechanism of action is still not completely understood. In the present study, the effects of metformin on gene and protein expression were investigated in pre- and postmenopausal EC in vitro models in order to identify candidates that are potentially involved in the drug's anti-cancer mechanism. Design After treating the cells with metformin (0.1 and 1.0 mmol/L), changes in the expression of >160 cancer- and metastasis-related gene transcripts were evaluated with RNA arrays. A total of 19 genes and 7 proteins were selected for a follow-up expression analysis, including further treatment conditions, in order to evaluate the influence of hyperinsulinemia and hyperglycemia on metformin-induced effects. Results Changes in the expression of BCL2L11, CDH1, CDKN1A, COL1A1, PTEN, MMP9 and TIMP2 were analyzed on gene and protein level. The consequences resulting from the detected expression changes as well as the influence of varying environmental influences are discussed in detail. With the presented data, we contribute to a better understanding of the direct anti-cancer activity of metformin as well as its underlying mechanism of action in EC cells. Conclusions Although further research will be necessary to confirm the data, the influence of different environmental settings on metformin-induced effects could be highlighted with the presented data. Additionally, gene and protein regulation were not similar in the pre- and postmenopausal in vitro models.
Collapse
|
|
14
|
Krakowski I, Häbel H, Nielsen K, Ingvar C, Andersson TML, Girnita A, Smedby KE, Eriksson H. Association of metformin use and survival in patients with cutaneous melanoma and diabetes. Br J Dermatol 2023; 188:32-40. [PMID: 36689497 DOI: 10.1093/bjd/ljac003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/19/2022] [Accepted: 09/03/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive. OBJECTIVES To investigate the association between metformin use and survival among patients with CM and diabetes. METHODS All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses. RESULTS Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4-6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57-0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86-0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97-0.98) for 0-6 months to 0.59 (0.49-0.70) for 24-30 months of use. No association was found for metformin use and MSS. CONCLUSIONS Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose-response pattern. However, further research regarding the underlying mechanisms is warranted.
Collapse
Affiliation(s)
- Isabelle Krakowski
- Department of Dermatology/Inflammation Theme
- Department of Oncology and Pathology
| | | | - Kari Nielsen
- Dermatology and Department of Dermatology, Skåne University Hospital, Lund, Sweden
| | - Christian Ingvar
- Surgery, Department of Clinical Sciences, Lund University, Lund, Sweden
| | | | - Ada Girnita
- Department of Oncology and Pathology
- Cancer Theme, Medical Unit Head, Neck, Lung and Skin Cancer, Skin Cancer Center
| | - Karin E Smedby
- Department of Medicine Solna, Division of Clinical Epidemiology; Karolinska Institutet, Stockholm, Sweden
- Department of Hematology; Karolinska University Hospital, Stockholm, Sweden
| | - Hanna Eriksson
- Department of Oncology and Pathology
- Cancer Theme, Medical Unit Head, Neck, Lung and Skin Cancer, Skin Cancer Center
| |
Collapse
|
|
15
|
Metformin Induces Apoptosis in Human Pancreatic Cancer (PC) Cells Accompanied by Changes in the Levels of Histone Acetyltransferases (Particularly, p300/CBP-Associated Factor (PCAF) Protein Levels). Pharmaceuticals (Basel) 2023; 16:ph16010115. [PMID: 36678613 PMCID: PMC9863441 DOI: 10.3390/ph16010115] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/05/2022] [Accepted: 12/16/2022] [Indexed: 01/15/2023] Open
Abstract
Accumulating evidence (mainly from experimental research) suggests that metformin possesses anticancer properties through the induction of apoptosis and inhibition of the growth and proliferation of cancer cells. However, its effect on the enzymes responsible for histone acetylation status, which plays a key role in carcinogenesis, remains unclear. Therefore, the aim of our study was to evaluate the impact of metformin on histone acetyltransferases (HATs) (i.e., p300/CBP-associated factor (PCAF), p300, and CBP) and on histone deacetylases (HDACs) (i.e., SIRT-1 in human pancreatic cancer (PC) cell lines, 1.2B4, and PANC-1). The cells were exposed to metformin, an HAT inhibitor (HATi), or a combination of an HATi with metformin for 24, 48, or 72 h. Cell viability was determined using an MTT assay, and the percentage of early apoptotic cells was determined with an Annexin V-Cy3 Apoptosis Detection Assay Kit. Caspase-9 activity was also assessed. SIRT-1, PCAF, p300, and CBP expression were determined at the mRNA and protein levels using RT-PCR and Western blotting methods, respectively. Our results reveal an increase in caspase-9 in response to the metformin, indicating that it induced the apoptotic death of both 1.2B4 and PANC-1 cells. The number of cells in early apoptosis and the activity of caspase-9 decreased when treated with an HATi alone or a combination of an HATi with metformin, as compared to metformin alone. Moreover, metformin, an HATi, and a combination of an HATi with metformin also modified the mRNA expression of SIRT-1, PCAF, CBP, and p300. However, metformin did not change the expression of the studied genes in 1.2B4 cells. The results of the Western blot analysis showed that metformin diminished the protein expression of PCAF in both the 1.2B4 and PANC-1 cells. Hence, it appears possible that PCAF may be involved in the metformin-mediated apoptosis of PC cells.
Collapse
|
|
16
|
Sanati M, Aminyavari S, Mollazadeh H, Motamed-Sanaye A, Bibak B, Mohtashami E, Teng Y, Afshari AR, Sahebkar A. The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme. Curr Med Chem 2023; 30:857-877. [PMID: 35796457 DOI: 10.2174/0929867329666220707103525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/13/2022] [Accepted: 04/16/2022] [Indexed: 02/08/2023]
Abstract
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
Collapse
Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ali Motamed-Sanaye
- Student Research Committee, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Bahram Bibak
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA30322, USA
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
17
|
Elizalde-Velázquez GA, Gómez-Oliván LM, García-Medina S, Rosales-Pérez KE, Orozco-Hernández JM, Islas-Flores H, Galar-Martínez M, Hernández-Navarro MD. Chronic exposure to realistic concentrations of metformin prompts a neurotoxic response in Danio rerio adults. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 849:157888. [PMID: 35952892 DOI: 10.1016/j.scitotenv.2022.157888] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 06/15/2023]
Abstract
Metformin (MET) is among the most consumed drugs around the world, and thus, it is considered the uppermost drug in mass discharged into water settings. Nonetheless, data about the deleterious consequences of MET on water organisms are still scarce and require further investigation. Herein, we aimed to establish whether or not chronic exposure to MET (1, 20, and 40 μg/L) may alter the swimming behavior and induce neurotoxicity in Danio rerio adults. After 4 months of exposure, MET-exposed fish exhibited less swimming activity when compared to control fish. Moreover, compared with the control group, MET significantly inhibited the activity of AChE and induced oxidative damage in the brain of fish. Concerning gene expression, MET significantly upregulated the expression of Nrf1, Nrf2, BAX, p53, BACE1, APP, PSEN1, and downregulated CASP3 and CASP9. Although MET did not overexpress the CASP3 gene, we saw a meaningful rise in the activity of this enzyme in the blood of fish exposed to MET compared to the control group, which we then confirmed by a high number of apoptotic cells in the TUNEL assay. Our findings demonstrate that chronic exposure to MET may impair fish swimming behavior, making them more vulnerable to predators.
Collapse
Affiliation(s)
- Gustavo Axel Elizalde-Velázquez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - Leobardo Manuel Gómez-Oliván
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico.
| | - Sandra García-Medina
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu s/n y cerrada Manuel Stampa, Col. Industrial Vallejo, Ciudad de México CP 07700, Mexico
| | - Karina Elisa Rosales-Pérez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - José Manuel Orozco-Hernández
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - Hariz Islas-Flores
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - Marcela Galar-Martínez
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu s/n y cerrada Manuel Stampa, Col. Industrial Vallejo, Ciudad de México CP 07700, Mexico
| | - María Dolores Hernández-Navarro
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| |
Collapse
|
|
18
|
Metformin as a Potential Antitumor Agent. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2022-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Abstract
Some recent findings suggest that metformin, an oral antidiabetic drug, may have antitumor properties. Studies have shown that metformin can alter cell metabolism, both tumor and immune cells, which can greatly influence disease outcome. In this review, we discuss the potential mechanisms in which metformin can directly induce apoptosis of tumor cells as well as mechanisms in which metformin can elicit or enhance antitumor immune response.
Collapse
|
|
19
|
Feng Y, Jia B, Shen Z. Metformin and bladder cancer: Drug repurposing as a potential tool for novel therapy: A review. Medicine (Baltimore) 2022; 101:e31635. [PMID: 36397350 PMCID: PMC9666131 DOI: 10.1097/md.0000000000031635] [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] [Indexed: 11/18/2022] Open
Abstract
Bladder cancer (BC) is a common type of cancer worldwide. Currently, the gold standard treatment is transurethral resection of bladder tumor (TUR-Bt) accompanied by intravesical Bacillus Calmette-Guérin (BCG) instillation for patients with middle-to-high-risk non-muscle-invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in almost 50% of high risk cases, leading to NMIBC persistence or early recurrence. In these patients, the gold standard remains radical cystectomy; however, it can seriously affect the patients' quality of life. Moreover, for patients with muscle-invasive bladder cancer (MIBC), the 5-year survival rate after radical cystectomy with neoadjuvant chemotherapy remains low. Recent discoveries have paved the way for a new era in BC treatment. Metformin is the most widely used oral hypoglycemic drug in clinical practice, being mostly used in the treatment of type 2 diabetes. Epidemiological studies have demonstrated that metformin exerts a potentially positive effect on reducing the incidence and mortality of cancer; therefore, a increasing number of studies have investigated the potential anticancer effects of metformin and its mechanisms of action. This review aims to summarize the evidence for the role of metformin in bladder cancer therapy, including how metformin mediates bladder cancer cell apoptosis.
Collapse
Affiliation(s)
- Yunzhu Feng
- School of Clinical Medicine, Guizhou Medical University, Guiyang City, Guizhou Province, China
| | - Benzhong Jia
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, China
- * Correspondence: Benzhong Jia, Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang City 550004, Guizhou Province, China (e-mail: )
| | - Zhiyong Shen
- Department of Urology, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, China
| |
Collapse
|
|
20
|
Elizalde-Velázquez GA, Gómez-Oliván LM, Rosales-Pérez KE, Orozco-Hernández JM, García-Medina S, Islas-Flores H, Galar-Martínez M. Chronic exposure to environmentally relevant concentrations of guanylurea induces neurotoxicity of Danio rerio adults. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 819:153095. [PMID: 35038519 DOI: 10.1016/j.scitotenv.2022.153095] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/07/2022] [Accepted: 01/09/2022] [Indexed: 06/14/2023]
Abstract
Recent studies have shown guanylurea (GUA) alters the growth and development of fish, induces oxidative stress, and disrupts the levels and expression of several genes, metabolites, and proteins related to the overall fitness of fish. Nonetheless, up to date, no study has assessed the potential neurotoxic effects that GUA may induce in non-target organisms. To fill the current knowledge gaps about the effects of this metabolite in the central nervous system of fish, we aimed to determine whether or not environmentally relevant concentrations of this metabolite may disrupt the behavior, redox status, AChE activity in Danio rerio adults. In addition, we also meant to assess if 25, 50, and 200 μg/L of GUA can alter the expression of several antioxidant defenses-, apoptosis-, AMPK pathway-, and neuronal communication-related genes in the brain of fish exposed for four months to GUA. Our results demonstrated that chronic exposure to GUA altered the swimming behavior of D. rerio, as fish remained more time frozen and traveled less distance in the tank compared to the control group. Moreover, this metabolite significantly increased the levels of oxidative damage biomarkers and inhibited the activity of acetylcholinesterase of fish in a concentration-dependent manner. Concerning gene expression, environmentally relevant concentrations of GUA downregulated the expression GRID2IP, PCDH17, and PCDH19, but upregulated Nrf1, Nrf2, p53, BAX, CASP3, PRKAA1, PRKAA2, and APP in fish after four months of exposure. Collectively, we can conclude that GUA may alter the homeostasis of several essential brain biomarkers, generating anxiety-like behavior in fish.
Collapse
Affiliation(s)
- Gustavo Axel Elizalde-Velázquez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - Leobardo Manuel Gómez-Oliván
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico.
| | - Karina Elisa Rosales-Pérez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - José Manuel Orozco-Hernández
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - Sandra García-Medina
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu s/n y cerrada Manuel Stampa, Col. Industrial Vallejo, Ciudad de México, CP 07700, Mexico
| | - Hariz Islas-Flores
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, CP 50120 Toluca, Estado de México, Mexico
| | - Marcela Galar-Martínez
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu s/n y cerrada Manuel Stampa, Col. Industrial Vallejo, Ciudad de México, CP 07700, Mexico
| |
Collapse
|
|
21
|
Forsati P, Pazhang Y. Mesalazine induces apoptosis via mitochondrial pathway in K562 cell line. VETERINARY RESEARCH FORUM : AN INTERNATIONAL QUARTERLY JOURNAL 2022; 13:121-126. [PMID: 35601773 PMCID: PMC9094592 DOI: 10.30466/vrf.2020.117585.2788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/12/2020] [Indexed: 11/24/2022]
Abstract
Inflammation is an initial response of the body to infection and relationship between inflammation and cancer has been established. Nuclear factor kappa B (NF-κB) is a central factor in inflammation and its activity contributes to tumor progression and apoptosis prevention consequently leading to cancer promotion. As a result, NF-κB inhibitors can cause apoptosis. In this study, the effect of mesalazine as a NF-κB inhibitor on growth and apoptosis of K562 cells has been investigated. The K562 cells were first cultured in RPMI-1640 medium containing 10.00% fetal bovine serum. After that, they were treated for 72 hr with different concentrations of mesalazine (20.00, 40.00, 60.00 and 80.00 μM mL-1). The MTT assay was used to evaluate cell viability. Hoechst staining and RT-PCR of apoptosis related genes (Bcl-2 and Bax) were carried out to illustrate apoptosis induction and immunocytochemistry was performed to investigate changes in c-Myc protein level. According to the results of MTT assay, all of applied mesalazine concentrations decreased K562 cells viability. Hoechst staining showed that the fragmented nuclei increased indicating apoptosis induction. Immuno-cytochemical results showed that mesalazine decreased c-Myc in treated cells. The RT-PCR results also showed an increase in Bax and a decrease in Bcl-2 expressions in mesalazine-treated cells. As the results suggest, mesalazine reduces cell viability by inducing apoptosis in K562 cell line; therefore, it can be used as a candidate for the leukemia treatment.
Collapse
Affiliation(s)
| | - Yaghub Pazhang
- Correspondence Yaghub Pazhang. PhD, Department of Biology, Faculty of Sciences, Urmia University, Urmia, Iran. E-mail:
| |
Collapse
|
|
22
|
Pretta A, Ziranu P, Puzzoni M, Lai E, Orsi G, Liscia N, Molinaro E, Mariani S, Riggi L, Rovesti G, Dubois M, Migliari M, Persano M, Saba G, Impera V, Musio F, Batzella E, Demurtas L, Pusceddu V, Astara G, Faloppi L, Casadei Gardini A, Andrikou K, Cascinu S, Scartozzi M. Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus. TUMORI JOURNAL 2021; 107:550-555. [PMID: 33243068 DOI: 10.1177/0300891620976945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. METHODS We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. RESULTS In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p = 0.03). CONCLUSIONS Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
Collapse
Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Molinaro
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Laura Riggi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Erich Batzella
- Department of Statistical Science, University of Padova, Padova, Veneto, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Macerata General Hospital, Macerata, Italy
| | - Andrea Casadei Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Cascinu
- IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| |
Collapse
|
|
23
|
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.
Collapse
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
| |
Collapse
|
|
24
|
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: 30] [Impact Index Per Article: 7.5] [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.
Collapse
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
| |
Collapse
|
|
25
|
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.
Collapse
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
| |
Collapse
|
|
26
|
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.
Collapse
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
| |
Collapse
|
|
27
|
Vitali E, Boemi I, Tarantola G, Piccini S, Zerbi A, Veronesi G, Baldelli R, Mazziotti G, Smiroldo V, Lavezzi E, Spada A, Mantovani G, Lania AG. Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment. Cancers (Basel) 2020; 12:2143. [PMID: 32748870 PMCID: PMC7464161 DOI: 10.3390/cancers12082143] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Treatment options for neuroendocrine tumors (NETs) are rarely curative, as NETs frequently show resistance to medical therapy. The use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signaling. In this context, the antidiabetic drug metformin is able to inhibit mTOR, providing a rationale for the use of metformin and everolimus in combination. METHODS We investigated the effects of the metformin and everolimus combination on NET cell proliferation, apoptosis, colony formation, cell viability, NET spheroids growth and the involvement of the Akt and mTOR pathways, and also developed everolimus-resistant NET cells to further study this combination. RESULTS Metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic NET (PAN-NET) cell proliferation (-71% ± 13%, p < 0.0001 vs. basal), whereas no additive effects were observed on pulmonary neuroendocrine tumor (PNT) cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation, cell viability, NET spheroids growth rate and mTOR phosphorylation in both NET cell lines. In a PAN-NET cell line, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in a PNT cell line. Using everolimus-resistant NET cells, we confirmed that metformin maintained its effects, acting by two different pathways: Akt-dependent or independent, depending on the cell type, with both leading to mTOR suppression. CONCLUSIONS Considering the promising effects of the everolimus and metformin combination in NET cells, our results provide a rationale for its use in NET patients.
Collapse
Affiliation(s)
- Eleonora Vitali
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.)
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
| | - Ilena Boemi
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.)
| | - Giulia Tarantola
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.)
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
| | - Sara Piccini
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.)
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
| | - Alessandro Zerbi
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
- Pancreas Surgery Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy
| | - Giulia Veronesi
- School of Medicine, Vita-Salute San Raffaele University, 20100 Milan, Italy;
- Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, 20100 Milan, Italy
| | - Roberto Baldelli
- Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, 13449 Rome, Italy;
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
- Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
| | - Valeria Smiroldo
- Oncology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
| | - Elisabetta Lavezzi
- Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
| | - Anna Spada
- Department of Clinical Sciences and Community Health, University of Milan, 20100 Milan, Italy; (A.S.); (G.M.)
| | - Giovanna Mantovani
- Department of Clinical Sciences and Community Health, University of Milan, 20100 Milan, Italy; (A.S.); (G.M.)
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy
| | - Andrea G. Lania
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
- Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
| |
Collapse
|
|
28
|
Arici M, Abudayyak M, Boran T, Özhan G. Does pendimethalin develop in pancreatic cancer induced inflammation? CHEMOSPHERE 2020; 252:126644. [PMID: 32443284 DOI: 10.1016/j.chemosphere.2020.126644] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 05/12/2023]
Abstract
Pendimethalin, one of the dinitroaniline group herbicides, is applied for controlling weeds in cereals, legumes and vegetable crops, and has been classified as possible human carcinogen. It is indicated that pendimethalin should arise risks of developing some cancer types; however, there is no data on the effects of pendimethalin on pancreatic cancer-induced inflammation. Injuries resulting from by acute pancreatitis attacks and inflammation are significant factors in the development of pancreatic cancer. Therefore, we investigated whether pendimethalin triggers inflammation as a mechanism of pancreatic cancer development. Parameters related to pancreatic activation, oxidative stress, and inflammation were measured in the human pancreatic (PANC-1) cell line. In the range of 0-100 μM, the levels of chymotrypsin decreased. It should be indicated that the reason for the decrease in chymotrypsin may be the high rates of cell death (20%) observed in the high concentration levels. We observed that pendimethalin significantly induced oxidative damage, while levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) did not change. The obtained results may draw attention to the usage and possible toxic effect of pendimethalin due to oxidative damage induction; however, detailed inflammation mechanisms and other cancer pathways should be investigated.
Collapse
Affiliation(s)
- M Arici
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - M Abudayyak
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - T Boran
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - G Özhan
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
| |
Collapse
|
|
29
|
Vitali E, Boemi I, Piccini S, Tarantola G, Smiroldo V, Lavezzi E, Brambilla T, Zerbi A, Carnaghi C, Mantovani G, Spada A, Lania AG. A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells. Mol Cell Endocrinol 2020; 509:110803. [PMID: 32251713 DOI: 10.1016/j.mce.2020.110803] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 03/24/2020] [Accepted: 03/29/2020] [Indexed: 12/12/2022]
Abstract
The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (-31 ± 12%, p < 0.05 vs basal at 100 μM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (-62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin.
Collapse
Affiliation(s)
- E Vitali
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.
| | - I Boemi
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - S Piccini
- Endocrinology and Diabetology Unit Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
| | - G Tarantola
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
| | - V Smiroldo
- Oncology Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - E Lavezzi
- Endocrinology and Diabetology Unit Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - T Brambilla
- Department of Pathology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - A Zerbi
- Pancreas Surgery Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - C Carnaghi
- Oncology Unit, Bolzano Hospital, Bolzano, Italy
| | - G Mantovani
- Endocrinology and Diabetology Unit, IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - A Spada
- Endocrinology and Diabetology Unit, IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - A G Lania
- Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy; Endocrinology and Diabetology Unit Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
| |
Collapse
|
|
30
|
Metformin-loaded chitosomes for treatment of malignant pleural mesothelioma - A rare thoracic cancer. Int J Biol Macromol 2020; 160:128-141. [PMID: 32445818 DOI: 10.1016/j.ijbiomac.2020.05.146] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/05/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023]
Abstract
The purpose of this study was to design and evaluate chitosan dispersed lipid vesicles (chitosomes) as potential delivery carriers for repurposing metformin (Met) against malignant pleural mesothelioma. Chitosomes were prepared by directly hydrating the thin lipid film using chitosan solution as hydration medium, instead of using it as a coating agent. Developed chitosomes demonstrated spherical morphology, positive surface charge (~30 mV) and ~60% encapsulation efficiency. The calorimetric studies and X-ray diffraction pattern of Met-loaded chitosomes confirmed the successful encapsulation of Met inside the chitosome vesicles. Optimized chitosome formulation showed ~70% drug release in 72 h, displaying prolonged and controlled release of drug. Results demonstrated that Met encapsulated chitosomes possessed enhanced cellular internalization and improved cytotoxic potential. Our findings also supported inhibitory activity of chitosomes against metastatic property of pleural mesothelioma cells. The in-vitro tumor simulation studies further established anti-tumor activity of Met encapsulated chitosomes as supported by reduction in tumor volume and presence of minimal viable cells in tumor mass. The obtained results establish the effectiveness of chitosomes as delivery carrier for Met as treatment alternative for malignant pleural mesothelioma.
Collapse
|
|
31
|
Broadhurst PJ, Hart AR. An observational study to justify and plan a future phase III randomized controlled trial of metformin in improving overall survival in patients with inoperable pancreatic cancer without liver metastases. J Cancer Res Clin Oncol 2020; 146:1369-1375. [PMID: 32157435 DOI: 10.1007/s00432-020-03177-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/03/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Metformin has plausible direct and indirect anti-cancer properties against pancreatic adenocarcinoma cells. However, metformin may only be efficacious in patients with inoperable pancreatic ductal adenocarcinoma (PDAC) without liver metastases. Absorption may be decreased by gastrointestinal symptoms and proton pump inhibitors (PPIs). We aimed to justify and inform a future phase III trial of metformin versus placebo on survival in inoperable PDAC by documenting prevalence of patients meeting eligibility criteria, gastrointestinal symptoms and PPI use. METHODS Patient notes with PDAC were reviewed at a large teaching hospital over 2 years. Study variables were obtained from multiple sources of information. RESULTS 141 participants were identified (51.8% female), of which 37.6% were not prescribed metformin at diagnosis and had no radiological hepatic metastases. Characteristics were similar between non-metformin and metformin users. In eligible patients, 65.2% reported nausea and vomiting and 46.2% were prescribed PPIs. CONCLUSION Approximately, a third of all patients with inoperable PDAC are eligible for a future trial of metformin, allowing an estimate of the number of hospitals required for recruitment. Nausea and vomiting are common and should be managed effectively to prevent trial dropouts. PPI use is frequent and their influence on metformin's pharmacodynamic actions needs to be clarified.
Collapse
Affiliation(s)
| | - Andrew R Hart
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK
- Norfolk and Norwich University Hospital NHS Trust, Norwich, NR4 7TJ, UK
| |
Collapse
|
|
32
|
Zhao Y, Zeng X, Tang H, Ye D, Liu J. Combination of metformin and paclitaxel suppresses proliferation and induces apoptosis of human prostate cancer cells via oxidative stress and targeting the mitochondria-dependent pathway. Oncol Lett 2019; 17:4277-4284. [PMID: 30944622 PMCID: PMC6444335 DOI: 10.3892/ol.2019.10119] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 01/22/2019] [Indexed: 12/22/2022] Open
Abstract
Previous studies have reported that metformin (MET) has anticancer activity. In combination with chemotherapeutic drugs, MET reduces the dosage of chemotherapeutic drugs required and enhances anticancer efficacy. In the present study, the combination of MET and paclitaxel (PTX) in three human prostate cancer (PCa) cell lines (22RV1, PC-3 and LNCaP) was evaluated to investigate the effects on proliferation and apoptosis of PCa cells. The present study explored whether their effects were associated with reactive oxygen species (ROS). An MTT assay and microscopy were used to study the effect of MET + PTX on cell growth. Half maximal inhibitory concentration (IC50) values were obtained for MET (12.281±1.089 mM for 22RV1, 2.248±0.352 mM for PC-3 cells and 3.610±0.577 mM for LNCaP cells) and PTX (13.170±1.12 nM for PC-3 cells) at 48 h. Since the survival rate of 22RV1 and LNCaP cells did not decrease linearly with increasing PTX concentration, it is difficult to estimate accurate IC50; therefore, only IC50 values for PTX in PC-3 cells were given. When treating the cells with 5 mM MET, the IC50 of PTX decreased to 5.423±0.734 nM for PC-3 cells. Annexin V and propidium iodide staining was used to investigate apoptosis by flow cytometry. The apoptotic mechanisms of MET + PTX in PCa were investigated by detecting the expression of apoptosis-related proteins, activities of caspase-3/7, intracellular ROS accumulation, mitochondrial membrane potential, and intracellular levels of adenosine 5′-triphosphate (ATP). MET + PTX induced PCa apoptosis and ROS accumulation, and decreased mitochondrial membrane potential and intracellular levels of ATP. Taken together, these results indicated that MET + PTX suppressed PCa cell proliferation in a dose- and time-dependent manner. In addition, MET + PTX induced apoptosis by increasing ROS levels, reducing mitochondrial membrane potential, and activating mitochondrial-dependent apoptotic pathways.
Collapse
Affiliation(s)
- Yuwan Zhao
- Laboratory of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Xin Zeng
- Laboratory of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Huancheng Tang
- Laboratory of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Dongcai Ye
- Laboratory of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Jianjun Liu
- Laboratory of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| |
Collapse
|
|
33
|
Lee JS, Sul JY, Park JB, Lee MS, Cha EY, Ko YB. Honokiol induces apoptosis and suppresses migration and invasion of ovarian carcinoma cells via AMPK/mTOR signaling pathway. Int J Mol Med 2019; 43:1969-1978. [PMID: 30864681 PMCID: PMC6443331 DOI: 10.3892/ijmm.2019.4122] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 02/18/2019] [Indexed: 01/08/2023] Open
Abstract
Honokiol, a natural biphenolic compound, exerts anticancer effects through a variety of mechanisms on multiple types of cancer with relatively low toxicity. Adenosine 5'‑phosphate‑activated protein kinase (AMPK), an essential regulator of cellular homeostasis, may control cancer progression. The present study aimed to investigate whether the anticancer activities of honokiol in ovarian cancer cells were mediated through the activation of AMPK. Honokiol decreased cell viability of 2 ovarian cancer cell lines, with an half‑maximal inhibitory concentration value of 48.71±11.31 µM for SKOV3 cells and 46.42±5.37 µM for Caov‑3 cells. Honokiol induced apoptosis via activation of caspase‑3, caspase‑7 and caspase‑9, and cleavage of poly‑(adenosine 5'‑diphosphate‑ribose) polymerase. Apoptosis induced by honokiol was weakened by compound C, an AMPK inhibitor, suggesting that honokiol‑induced apoptosis was dependent on the AMPK/mechanistic target of rapamycin signaling pathway. Additionally, honokiol inhibited the migration and invasion of ovarian cancer cells. The combined treatment of honokiol with compound C reversed the activities of honokiol in wound healing and Matrigel invasion assays. These results indicated that honokiol may have therapeutic potential in ovarian cancer by targeting AMPK activation.
Collapse
Affiliation(s)
- Jin Sun Lee
- Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Ji Young Sul
- Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jun Beom Park
- Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Myung Sun Lee
- Surgical Oncology Research Laboratory, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Eun Young Cha
- Surgical Oncology Research Laboratory, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Young Bok Ko
- Research Institute for Medicinal Sciences, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| |
Collapse
|
|
34
|
Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, Favre C. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep 2019; 9:2815. [PMID: 30809021 PMCID: PMC6391381 DOI: 10.1038/s41598-019-39556-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 01/17/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly metastatic cancer with very poor prognosis. AMP activated kinase (AMPK) constitutes a candidate to inhibit HCC progression. First, AMPK is downregulated in HCC. Second, glucose starvation induces apoptosis in HCC cells via AMPK. Correspondingly, metformin activates AMPK and inhibits HCC cell proliferation. Nevertheless, the effect of AMPK activation on HCC cell invasiveness remains elusive. Here, migration/invasion was studied in HCC cells exposed to metformin and glucose starvation. Cell viability, proliferation and differentiation, as well as AMPK and PKA activation were analyzed. In addition, invasiveness in mutants of the AMPKα activation loop was assessed. Metformin decreased cell migration, invasion and epithelial-mesenchymal transition, and interference with AMPKα expression avoided metformin actions. Those antitumor effects were potentiated by glucose deprivation. Metformin activated AMPK at the same time that inhibited PKA, and both effects were enhanced by glucose starvation. Given that AMPKα(S173) phosphorylation by PKA decreases AMPK activation, we hypothesized that the reduction of PKA inhibitory effect by metformin could explain the increased antitumor effects observed. Supporting this, in AMPK activating conditions, cell migration/invasion was further impaired in AMPKα(S173C) mutant cells. Metformin emerges as a strong inhibitor of migration/invasion in HCC cells, and glucose restriction potentiates this effect.
Collapse
Affiliation(s)
- Anabela C Ferretti
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Florencia Hidalgo
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Facundo M Tonucci
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Evangelina Almada
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Alejandro Pariani
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - María C Larocca
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina
| | - Cristián Favre
- Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
| |
Collapse
|
|
35
|
Abstract
IMPACT STATEMENT Cancer is among the leading causes of death worldwide. In 2016, 8.9 million people are estimated to have died from various forms of cancer. The current treatments, including surgery with chemotherapy and/or radiation therapy, are not effective enough to provide full protection from cancer, which highlights the need for developing novel therapy strategies. In this review, we summarize the molecular biology of a unique member of a subfamily of receptor tyrosine kinase, TYRO3 and discuss the new insights in TYRO3-targeted treatment for cancer therapy.
Collapse
Affiliation(s)
- Pei-Ling Hsu
- 1 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Jonathan Jou
- 2 College of Medicine, University of Illinois, IL 60612, USA
| | - Shaw-Jenq Tsai
- 1 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| |
Collapse
|
|
36
|
Broadhurst PJ, Hart AR. Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use. Dig Dis Sci 2018; 63:2840-2852. [PMID: 30159732 DOI: 10.1007/s10620-018-5233-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/31/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug-drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress.
Collapse
Affiliation(s)
| | - Andrew R Hart
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK.,Norfolk and Norwich University Hospital NHS Trust, University of East Anglia, Norwich, NR4 7TJ, UK
| |
Collapse
|
|
37
|
Bai M, Yang L, Liao H, Liang X, Xie B, Xiong J, Tao X, Chen X, Cheng Y, Chen X, Feng Y, Zhang Z, Zheng W. Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism. Oncogene 2018; 37:5666-5681. [PMID: 29921847 DOI: 10.1038/s41388-018-0360-7] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 05/19/2018] [Accepted: 05/25/2018] [Indexed: 02/07/2023]
Abstract
Chemoresistance is the major obstacle to cure endometrial cancer, whereas metformin has demonstrated sensitization to chemotherapy in endometrial cancer. A novel finding states that isocitrate dehydrogenase 1 (IDH1) involves in cancer chemoresistance. Recent studies have revealed that epigenetic modifications facilitate chemoresistance. However, whether IDH1 play a role in metformin-induced endometrial cancer chemosensitivity through epigenetic modification is incompletely understood. Immunohistochemistry and Elisa assays were used to evaluate the expression pattern of IDH1 in endometrial tissue and serum, respectively. Western blot was performed to determine changes in expression of key molecules in the IDH1-ɑ-KG-TET1-Nrf2 signaling pathway after various treatments. Dot blot assays were used to assess global hydroxymethylation levels after metformin administration or plasmid transfection. Antioxidant response element (ARE) activity in the IDH1 promoter region was monitored by luciferase assay. Cancer cell sensitivity to chemotherapy was detected by SRB assay. We found that activation of the IDH1 signaling pathway in endometrial cancer tissue resulting from aberrant expression of IDH1 and its downstream mediators conferred chemoresistance. We found that this effect was abated by metformin treatment. Dot blot and HMeDIP assays revealed that metformin blocked IDH1-ɑ-KG-TET1-mediated enhancement of Nrf2 hydroxymethylation levels, eliminating chemoresistance. Moreover, we observed that chemoresistance was enhanced via a regulatory loop in which Nrf2 activated IDH1-ɑ-KG-TET1-Nrf2 signaling via binding to the ARE sites in the IDH1 promoter region. Our findings highlight a critical role of IDH1-ɑ-KG-TET1-Nrf2 signaling in chemoresistance and suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.
Collapse
Affiliation(s)
- Mingzhu Bai
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China
| | - Linlin Yang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China.,Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Baoshan Branch, Shanghai, 201900, China
| | - Hong Liao
- Department of Cervical Diseases, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Xiaoyan Liang
- Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Baoshan Branch, Shanghai, 201900, China
| | - Bingying Xie
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China
| | - Ji Xiong
- Department of Pathology, Huashan Hospital of Fudan University, Shanghai, 200040, China
| | - Xiang Tao
- Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China
| | - Xiong Chen
- Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Baoshan Branch, Shanghai, 201900, China
| | - Yali Cheng
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China
| | - Xiaojun Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China
| | - Youji Feng
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China
| | - Zhenbo Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China. .,Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Baoshan Branch, Shanghai, 201900, China.
| | - Wenxin Zheng
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. .,Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
| |
Collapse
|
|
38
|
Songthaveesin C, Sa-Nongdej W, Limboonreung T, Chongthammakun S. Combination of metformin and 9-cis retinoic acid increases apoptosis in C6 glioma stem-like cells. Heliyon 2018; 4:e00638. [PMID: 29872770 PMCID: PMC5986546 DOI: 10.1016/j.heliyon.2018.e00638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 04/09/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022] Open
Abstract
Glioblastoma (GBM) is the most commonly diagnosed type of brain cancer and the leading cause of brain cancer-related death. GBM contains a subpopulation of tumor-propagating glioblastoma stem-like cells that are thought to drive cancer progression and recurrence. Although several clinical trials are ongoing to explore new chemotherapeutic agents to treat GBM, the use of metformin (Met), a first-line drug for type 2 diabetes mellitus, in cancer remains controversial. Here, we show that combining Met with 9-cis retinoic acid (9-cis RA) reduced the proliferation rate of C6-GSCs (glioblastoma stem-like cells) in vitro. The results of flow cytometric analysis showed that treatment with 9-cis RA for 24 h induced 4.5% early and 38.0% late apoptosis in C6-GSCs. Twenty-four hours of Met treatment induced 23.6% early and 33.5% late apoptosis in C6-GSCs. Combination of Met and 9-cis RA treatment significantly increased both early and late apoptosis to 30.4% and 55.4%, respectively. The present findings suggest that not only 9-cis RA but also Met has the potential to induce early and late apoptotic GSCs death by affecting the functional cytoplasmic and nuclear organelles. At the protein level, there was increased cleaved caspase-3 but decreased procaspase-3 expression in Met-, 9-cis RA- and Met+9-cis RA-treated C6 GSCs, as detected by western blotting. The ratio of cleaved caspase-3/procaspase-3 was 1.6 times higher in Met+9-cis RA-treated groups compared to control. Ultimately, a combination of Met and 9-cis RA might be a possible therapeutic target for the treatment of GBM.
Collapse
Affiliation(s)
- Chanchai Songthaveesin
- Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Wanna Sa-Nongdej
- School of Nursing, Ramathibodi Hospital, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Tanapol Limboonreung
- Department of Anatomy and Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Sukumal Chongthammakun
- Department of Anatomy and Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| |
Collapse
|
|
39
|
Sena P, Mancini S, Benincasa M, Mariani F, Palumbo C, Roncucci L. Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings. Int J Mol Sci 2018; 19:1478. [PMID: 29772687 PMCID: PMC5983851 DOI: 10.3390/ijms19051478] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/25/2018] [Accepted: 05/10/2018] [Indexed: 12/25/2022] Open
Abstract
Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer.
Collapse
Affiliation(s)
- Paola Sena
- Department of Biomedical, Metabolic and Neurosciences, Section of Human Morphology, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Stefano Mancini
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Marta Benincasa
- Department of Biomedical, Metabolic and Neurosciences, Section of Human Morphology, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Francesco Mariani
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Carla Palumbo
- Department of Biomedical, Metabolic and Neurosciences, Section of Human Morphology, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| | - Luca Roncucci
- Department of Diagnostic and Clinical Medicine, and Public Health, University of Modena and Reggio Emilia, Policlinico, Via Del Pozzo 71, I-41125 Modena, Italy.
| |
Collapse
|
|
40
|
Bellahcène A, Nokin MJ, Castronovo V, Schalkwijk C. Methylglyoxal-derived stress: An emerging biological factor involved in the onset and progression of cancer. Semin Cancer Biol 2018; 49:64-74. [DOI: 10.1016/j.semcancer.2017.05.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/18/2017] [Accepted: 05/22/2017] [Indexed: 02/07/2023]
|
|
41
|
McCubrey JA, Lertpiriyapong K, Steelman LS, Abrams SL, Yang LV, Murata RM, Rosalen PL, Scalisi A, Neri LM, Cocco L, Ratti S, Martelli AM, Laidler P, Dulińska-Litewka J, Rakus D, Gizak A, Lombardi P, Nicoletti F, Candido S, Libra M, Montalto G, Cervello M. Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging (Albany NY) 2018; 9:1477-1536. [PMID: 28611316 PMCID: PMC5509453 DOI: 10.18632/aging.101250] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 06/04/2017] [Indexed: 02/07/2023]
Abstract
Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the treatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.
Collapse
Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Steve L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Ramiro M Murata
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.,Department of Foundational Sciences, School of Dental Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Pedro L Rosalen
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil
| | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Stefano Ratti
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Piotr Laidler
- Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland
| | | | - Dariusz Rakus
- Department of Animal Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | | | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.,Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| |
Collapse
|
|
42
|
Metformin inhibits proliferation and growth hormone secretion of GH3 pituitary adenoma cells. Oncotarget 2018; 8:37538-37549. [PMID: 28380462 PMCID: PMC5514928 DOI: 10.18632/oncotarget.16556] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 02/06/2017] [Indexed: 12/16/2022] Open
Abstract
Metformin is an anti-hyperglycemic agent used to treat diabetes, and recent evidence suggests it has antitumor efficacy. Because growth hormone-secreting pituitary adenoma (GH-PA) patients have a high incidence of diabetes frequently treated with metformin, we assessed the antitumor effect of metformin on GH-PA. We found that metformin effectively inhibited proliferation and induced apoptosis in the GH-PA cell line GH3. We detected a decrease in mitochondrial membrane potential (MMP), an increase in expression of pro-apoptotic proteins, and a decrease in expression of an anti-apoptotic protein in metformin-treated GH3 cells, which suggests involvement of the mitochondrial-mediated apoptosis pathway. Inhibition of AMPK, which is activated by metformin, failed to reverse the antiproliferative effect. ATF3 was upregulated by metformin, and its knockdown significantly reduced metformin-induced apoptosis. In addition, GH secretion was inhibited by metformin through suppression of STAT3 activity independently of AMPK. Metformin also significantly suppressed cellular proliferation and GH secretion in primary human GH-PA cells. Metformin also significantly inhibited GH3 cell proliferation and GH secretion in vivo. ATF3 upregulation and p-STAT3 downregulation were confirmed in xenografts. These findings suggest metformin is a potentially promising therapeutic agent for the treatment of GH-PA, particularly in patients with diabetes.
Collapse
|
|
43
|
Ding J, Zhu YT, Yang L, Tang J, Wang YY, Chen Y, Cheng K, Liu JQ, Zhang YN, Li ZK, Du Y, Qiu M, Liu JY. 14-3-3zeta is involved in the anticancer effect of metformin in colorectal carcinoma. Carcinogenesis 2018; 39:493-502. [PMID: 29390122 DOI: 10.1093/carcin/bgy008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Metformin is a promising drug for cancer prevention and treatment, especially in the diabetic population. We aimed to test whether 14-3-3zeta affects the anticancer effect of metformin on colorectal carcinoma (CRC). In this study, we confirmed that higher 14-3-3zeta expression was found in CRC tissues than in pericarcinoma tissues, and in CRC tissue of patients with diabetes than in those without diabetes. A knockdown of 14-3-3zeta inhibited CRC proliferation and promoted apoptosis in vitro and in vivo. Then, we created stable cell lines with under-expressed 14-3-3zeta from SW480 and HCT15 cells after infection by a lentiviral vector carrying short hairpin RNA targeting 14-3-3zeta (named LV-sh14-3-3zeta). Of note, metformin induced apoptosis and retarded tumor growth in the CRCs with overexpressed 14-3-3zeta, whereas this action was attenuated when 14-3-3zeta was knocked down. Moreover, either metformin or downregulation of 14-3-3zeta noticeably activated AMP-dependent protein kinase (AMPK) signaling, whereas the effect of metformin was attenuated when the 14-3-3zeta expression was decreased. Taken together, our results suggest that 14-3-3zeta may be associated with carcinogenesis and poor prognosis of CRCs associated with diabetes, and metformin may reverse the AMPK inhibition caused by 14-3-3zeta in CRCs in the background of diabetes. Our study should lead to a better understanding of the anticancer activity of metformin and points to possible application of metformin to the treatment of cancers overexpressing 14-3-3zeta.
Collapse
Affiliation(s)
- Jing Ding
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
- Department of Oncology, Cancer Hospital Affiliate to School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yue-Ting Zhu
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Lie Yang
- Department of Gastrointestinal Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Jie Tang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Yu-Yi Wang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Ye Chen
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Ke Cheng
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Jia-Qi Liu
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Yun-Ni Zhang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhi-Ke Li
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Yang Du
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Meng Qiu
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Ji-Yan Liu
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| |
Collapse
|
|
44
|
Nazim UM, Moon JH, Lee JH, Lee YJ, Seol JW, Eo SK, Lee JH, Park SY. Activation of autophagy flux by metformin downregulates cellular FLICE-like inhibitory protein and enhances TRAIL- induced apoptosis. Oncotarget 2018; 7:23468-81. [PMID: 26992204 PMCID: PMC5029640 DOI: 10.18632/oncotarget.8048] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 02/29/2016] [Indexed: 02/06/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL is regarded as one of the most promising anticancer agents, because it can destruct cancer cells without showing any toxicity to normal cells. Metformin is an anti-diabetic drug with anticancer activity by inhibiting tumor cell proliferation. In this study, we demonstrated that metformin could induce TRAIL-mediated apoptotic cell death in TRAIL-resistant human lung adenocarcinoma A549 cells. Pretreatment of metformindownregulation of c-FLIP and markedly enhanced TRAIL-induced tumor cell death by dose-dependent manner. Treatment with metformin resulted in slight increase in the accumulation of microtubule-associated protein light chain LC3-II and significantly decreased the p62 protein levels by dose-dependent manner indicated that metformin induced autophagy flux activation in the lung cancer cells. Inhibition of autophagy flux using a specific inhibitor and genetically modified ATG5 siRNA blocked the metformin-mediated enhancing effect of TRAIL. These data demonstrated that downregulation of c-FLIP by metformin enhanced TRAIL-induced tumor cell death via activating autophagy flux in TRAIL-resistant lung cancer cells and also suggest that metformin may be a successful combination therapeutic strategy with TRAIL in TRAIL-resistant cancer cells including lung adenocarcinoma cells.
Collapse
Affiliation(s)
- Uddin Md Nazim
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Ji-Hong Moon
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Ju-Hee Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - You-Jin Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Jae-Won Seol
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Seong-Kug Eo
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - John-Hwa Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| | - Sang-Youel Park
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
| |
Collapse
|
|
45
|
Abstract
Metformin is the most common biguanide used in the treatment of diabetes, with 120 million treated patients worldwide. Metformin decreases hyperglycemia without inducing hypoglycemia in diabetic patients and is very well tolerated. The principal effects of metformin are to decrease hepatic gluconeogenesis and increase glucose absorption by skeletal muscles. These effects are primarily due to metformin's action on mitochondria, which requires the activation of metabolic checkpoint AMP-activated protein kinase (AMPK). AMPK is implicated in several pathways, and following metformin activation, it decreases protein synthesis and cell proliferation. Many studies have examined the role of metformin in the regulation of cancer cells, particularly its effects on cancer cell proliferation and cell death. Encouraging results have been obtained in different types of cancers, including prostate, breast, lung, and skin cancers (melanoma). Furthermore, many retrospective epidemiological studies in diabetes patients have shown that metformin treatment decreased the risk of cancers compared with other antidiabetic treatments. In this review, we will discuss the effects of metformin on melanoma cells. Together, our novel data demonstrate the importance of developing metformin and new biguanide-derived compounds as potential treatments against a number of different cancers, particularly melanoma.
Collapse
Affiliation(s)
- Emilie Jaune
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
- Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France
| | - Stéphane Rocchi
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
- Université de Nice Sophia Antipolis, UFR de Médecine, Nice, France
- *Correspondence: Stéphane Rocchi
| |
Collapse
|
|
46
|
Biondani G, Peyron JF. Metformin, an Anti-diabetic Drug to Target Leukemia. Front Endocrinol (Lausanne) 2018; 9:446. [PMID: 30147674 PMCID: PMC6095966 DOI: 10.3389/fendo.2018.00446] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 07/19/2018] [Indexed: 12/14/2022] Open
Abstract
Metformin, a widely used anti-diabetic molecule, has attracted a strong interest in the last 10 years as a possible new anti-cancer molecule. Metformin acts by interfering with mitochondrial respiration, leading to an activation of the AMPK tumor-suppressive pathway to promote catabolic-energy saving reactions and block anabolic ones that are associated with abnormal cell proliferation. Metformin also acts at the organism level. In type 2 diabetes patients, metformin reduces hyperglycemia and increases insulin sensitivity by enhancing insulin-stimulated glucose uptake in muscles, liver, and adipose tissue and by reducing glucose output by the liver. Lowering insulin and insulin-like growth factor 1 (IGF-1) levels that stimulate cancer growth could be important features of metformin's mode of action. Despite continuous progress in treatments with the use of targeted therapies and now immunotherapies, acute leukemias are still of very poor prognosis for relapse patients, demonstrating an important need for new treatments deriving from the identification of their pathological supportive mechanisms. In the last decade, it has been realized that if cancer cells modify and reprogram their metabolism to feed their intense biochemical needs associated with their runaway proliferation, they develop metabolic addictions that could represent attractive targets for new therapeutic strategies that intend to starve and kill cancer cells. This Mini Review explores the anti-leukemic potential of metformin and its mode of action on leukemia metabolism.
Collapse
|
|
47
|
Wang X, Chen K, Yu Y, Xiang Y, Kim JH, Gong W, Huang J, Shi G, Li Q, Zhou M, Sayers T, Tewary P, Gao B, Wang JM. Metformin sensitizes lung cancer cells to treatment by the tyrosine kinase inhibitor erlotinib. Oncotarget 2017; 8:109068-109078. [PMID: 29312591 PMCID: PMC5752504 DOI: 10.18632/oncotarget.22596] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/21/2017] [Indexed: 02/05/2023] Open
Abstract
Lung cancer is one of the deadliest malignant tumors with limited treatment options. Although targeted therapy, using tyrosine-kinase inhibitors such as erlotinib (Erlo), has shown therapeutic benefit, only 15 % patients with mutated epidermal growth factor receptor (EGFR) in lung cancer cells are sensitive. Therefore, additional therapeutic strategy should be developed. In this study, we found that metformin (Met), which is widely used for the treatment of type 2 diabetes (T2D), sensitized lung cancer cells bearing wild-type EGFR to Erlo treatment by enriching cancer cells expressing higher levels of EGFR with persistent phosphorylation. As a consequence, combination of Met and Erlo more efficiently inhibited the growth of lung cancer cells both in vitro and in mice with xenografted tumors. Our results suggest a novel approach to treating lung cancer cases which are originally resistant to Erlo.
Collapse
Affiliation(s)
- Xiaofei Wang
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Keqiang Chen
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Ying Yu
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Eye Institute, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yi Xiang
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jae Hong Kim
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Jiaqiang Huang
- College of Life Sciences and Bioengineering, School of Sciences, Beijing Jiaoton University, Beijing 100044, China
| | - Guochao Shi
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Qingyun Li
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Min Zhou
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Thomas Sayers
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Poonam Tewary
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Beili Gao
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Ji Ming Wang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| |
Collapse
|
|
48
|
Zhu RC, Rattanakorn K, Pham S, Mallam D, McIntyre T, Salifu MO, Youssef I, McFarlane SI, Vignesh S. Survival benefits in colorectal adenocarcinoma with the use of metformin among a black diabetic inner city population. COLORECTAL CANCER 2017; 6:33-41. [PMID: 29308089 DOI: 10.2217/crc-2017-0001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
We assessed the association of metformin use with survival in colorectal cancer in a population consists mostly of African-American and Afro-Caribbean patients. We identified 585 colorectal cancer patients, 167 (28.6%) and 418 (71.5%) were as diabetic (DM) and nondiabetic, respectively. The diagnosis of diabetes did not impact cancer survival or extent of disease. Overall, DMs with metformin use (D+M+) have better overall survival than both DMs without metformin use (D+M∼) and nondiabetics (D∼M∼), with a mean survival of 109.9 months compared with 95.7 and 106.1 months, respectively (log-rank p < 0.05). The use of metformin shows significant reduction of risk of mortality compared with nonusers (hazard ratio: 0.34; 95% CI: 0.15-0.81; p = 0.01). Use of insulin and status of diabetes did not have a significant impact on overall cancer survival.
Collapse
Affiliation(s)
- Roger C Zhu
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Kirk Rattanakorn
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Steven Pham
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Divya Mallam
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Thomas McIntyre
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Moro O Salifu
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Irini Youssef
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Samy I McFarlane
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| | - Shivakumar Vignesh
- Department of Medicine, Divisions of Gastroenterology & Endocrinology, State University of New York, Downstate Medical Center & Kings County Hospital, Brooklyn, NY 11203, USA
| |
Collapse
|
|
49
|
Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. Oncotarget 2017; 8:56546-56557. [PMID: 28915611 PMCID: PMC5593582 DOI: 10.18632/oncotarget.17798] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/27/2017] [Indexed: 12/16/2022] Open
Abstract
Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR). Moreover, a treatment that combines 5-Fu and metformin was found to have a synergistic effect on the cell proliferation rate, especially in SNU-C5_5FuR, which was mediated by the activation of AMPK pathway and NF-ƙB pathway, well-known metformin mechanisms. In this study, we suggested novel anticancer mechanism of metformin that inhibited DNA replication machinery, such as the MCM family in SNU-C5_5FuR. In conclusion, we provided that how metformin acts as not only a chemo-sensitizer, but also as a synergistic effector of 5-Fu in the 5-Fu resistant-cell line. We speculate that metformin used for adjuvant therapy is effective on 5-Fu resistant cancer cells.
Collapse
|
|
50
|
Chiyo T, Kato K, Iwama H, Fujihara S, Fujita K, Tadokoro T, Ohura K, Samukawa E, Yamana Y, Kobayashi N, Matsunaga T, Nishiyama N, Ayaki M, Yachida T, Morishita A, Kobara H, Mori H, Masaki T. Therapeutic potential of the antidiabetic drug metformin in small bowel adenocarcinoma. Int J Oncol 2017; 50:2145-2153. [DOI: 10.3892/ijo.2017.3971] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 03/15/2017] [Indexed: 11/06/2022] Open
|