The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances

References

• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:10.1016/j.cell.2011.02.01321376230
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.10647931
   PubMed Web of Science ®Google Scholar
• Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2(6):57. doi:10.3978/j.issn.2305-5839.2014.06.0125333032
   PubMedGoogle Scholar
• Algaonker SS. Diabetes mellitus as seen in Ancient Ayurvedic Medicine. Bajaj AS, editor. Insulin and Metabolism. Bombay (India): Indian Press. 1972;13–20.
   Google Scholar
• Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–1576. doi:10.1007/s00125-017-4318-z28776081
   PubMed Web of Science ®Google Scholar
• Miles JM, Rule AD, Borlaug BA. Use of metformin in diseases of aging. Curr Diab Rep. 2014;14(6):490. doi:10.1007/s11892-014-0490-424752835
   PubMed Web of Science ®Google Scholar
• Gul W. Metformin: methods of analysis and its role in lowering the risk of cancer. J Bioequiv Availab. 2016;8:254–259. doi:10.4172/jbb
   Google Scholar
• Dawes G, Mott J. Circulatory and respiratory reflexes caused by aromatic guanidines. Br J Pharmacol Chemother. 1950;5(1):65–76.15405470
   PubMed Web of Science ®Google Scholar
• Suissa S, Azoulay L. Metformin and cancer: mounting evidence against an association. Diabetes Care. 2014;37(7):1786–1788. doi:10.2337/dc14-050024963109
   PubMed Web of Science ®Google Scholar
• Whitburn J, Edwards CM, Sooriakumaran P. Metformin and prostate cancer: a new role for an old drug. Curr Urol Rep. 2017;18(6):46. doi:10.1007/s11934-017-0693-828444639
   PubMed Web of Science ®Google Scholar
• Samsuri NAB, Leech M, Marignol L. Metformin and improved treatment outcomes in radiation therapy–A review. Cancer Treat Rev. 2017;55:150–162. doi:10.1016/j.ctrv.2017.03.00528399491
   PubMed Web of Science ®Google Scholar
• Watanabe C. Studies in the metabolic changes induced by administration of guanidine bases. II. The influence of guanidine upon urinary ammonia and acid secretion. J Biol Chem. 1918;34:51.
   Google Scholar
• Asmal AC, Marble A. Oral hypoglycaemic agents. Drugs. 1984;28(1):62–78. doi:10.2165/00003495-198428010-000046378583
   PubMed Web of Science ®Google Scholar
• Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122(6):253–270. doi:10.1042/CS2011038622117616
   PubMed Web of Science ®Google Scholar
• Cantoria MJC. The Effects of Metformin on Pancreatic Cancer Metabolism. 2014.
   Google Scholar
• Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9(1):33. doi:10.1186/1741-7015-9-3321470407
   PubMed Web of Science ®Google Scholar
• Malek M, Aghili R, Emami Z, Khamseh ME. Risk of cancer in diabetes: the effect of metformin. ISRN Endocrinol. 2013:2013.
   PubMedGoogle Scholar
• Rêgo DF, Pavan LMC, Elias ST, Canto GDL, Guerra ENS. Effects of metformin on head and neck cancer: a systematic review. Oral Oncol. 2015;51(5):416–422. doi:10.1016/j.oraloncology.2015.01.00725636350
   PubMed Web of Science ®Google Scholar
• Zaharenko L. Pharmacogenetics of Efficiency and Tolerance of the Peroral Antidiabetic Drug Metformin. Riga: University of Latvia; 2015.
   Google Scholar
• Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol. 2012;29(2):1314–1327. doi:10.1007/s12032-011-9846-721301998
   PubMed Web of Science ®Google Scholar
• Spillane SC, Bennett K, Sharp L, Barron TI. A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer .Cancer Epidemiol Prev Biomarkers. 2013 cebp. 0347.2013. doi:10.1158/1055-9965.EPI-13-0347
   PubMed Web of Science ®Google Scholar
• Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20(6):953–966. doi:10.1016/j.cmet.2014.09.01825456737
   PubMed Web of Science ®Google Scholar
• Muaddi H, Chowdhury S, Vellanki R, Zamiara P, Koritzinsky M. Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin. Radiother Oncol. 2013;108(3):446–450. doi:10.1016/j.radonc.2013.06.01423891087
   PubMed Web of Science ®Google Scholar
• Cantoria MJ, Patel H, Boros LG, Meuillet EJ; Metformin and Pancreatic Cancer Metabolism. Pancreatic Cancer-Insights into Molecular Mechanisms and Novel Approaches to Early Detection and Treatment. London, UK: IntechOpen; 2014.
   Google Scholar
• Del Barco S, Vazquez-Martin A, Cufí S, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2(12):896. doi:10.18632/oncotarget.24122203527
   PubMedGoogle Scholar
• Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550–554. doi:10.1056/NEJM1995083133309037623903
   PubMed Web of Science ®Google Scholar
• Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab. 2000;85(8):2767–2774. doi:10.1210/jcem.85.8.673810946879
   PubMed Web of Science ®Google Scholar
• Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res. 2011;2012.
   PubMedGoogle Scholar
• Ghatak SB, Dhamecha PS, Bhadada SV, Panchal SJ. Investigation of the potential effects of metformin on atherothrombotic risk factors in hyperlipidemic rats. Eur J Pharmacol. 2011;659(2–3):213–223. doi:10.1016/j.ejphar.2011.03.02921463616
   PubMed Web of Science ®Google Scholar
• Ou H-Y, Cheng J-T, Yu E, Wu T-J. Metformin increases insulin sensitivity and plasma β-endorphin in human subjects. Hormone Metab Res. 2006;38(02):106–111. doi:10.1055/s-2006-925128
   PubMedGoogle Scholar
• Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063–2069.11118008
   PubMed Web of Science ®Google Scholar
• Schatz H. Metformin in type 1 diabetes reduces insulin requirements without significantly improving glycaemic control. Diabetologia. 2010;53(10):2264–2265. doi:10.1007/s00125-010-1844-320617302
   PubMed Web of Science ®Google Scholar
• Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003–2015. doi:10.1056/NEJMoa070719318463376
   PubMed Web of Science ®Google Scholar
• Bianchi C, Penno G, Romero F, Del Prato S, Miccoli R. Treating the metabolic syndrome. Expert Rev Cardiovasc Ther. 2007;5(3):491–506. doi:10.1586/14779072.5.3.49117489673
   PubMedGoogle Scholar
• Diamanti‐Kandarakis E, Economou F, Palimeri S, Christakou C. Metformin in polycystic ovary syndrome. Ann N Y Acad Sci. 2010;1205(1):192–198. doi:10.1111/j.1749-6632.2010.05679.x20840272
   PubMedGoogle Scholar
• Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–226. doi:10.1016/j.molcel.2008.03.00318439900
   PubMed Web of Science ®Google Scholar
• Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005;40(8):685–693. doi:10.1016/j.exger.2005.07.00716125352
   PubMed Web of Science ®Google Scholar
• Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin–dependent translation initiation in breast cancer cells. Cancer Res. 2007;67(22):10804–10812. doi:10.1158/0008-5472.CAN-07-231018006825
   PubMed Web of Science ®Google Scholar
• Alimova IN, Liu B, Fan Z, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009;8(6):909–915. doi:10.4161/cc.8.6.793319221498
   PubMed Web of Science ®Google Scholar
• Ooi GT, Tseng L, Tran MQ, Rechler MM. Insulin rapidly decreases insulin-like growth factor-binding protein-1 gene transcription in streptozotocin-diabetic rats. Mol Endocrinol. 1992;6(12):2219–2228. doi:10.1210/mend.6.12.12834421283442
   PubMedGoogle Scholar
• Saito S, Furuno A, Sakurai J, et al. Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation. Cancer Res. 2009;69(10):4225–4234. doi:10.1158/0008-5472.CAN-08-268919435925
   PubMed Web of Science ®Google Scholar
• Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69(19):7507–7511. doi:10.1158/0008-5472.CAN-09-299419752085
   PubMed Web of Science ®Google Scholar
• Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem cello ntogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle. 2010;9(18):3831–3838. doi:10.4161/cc.9.19.1332420890113
   PubMed Web of Science ®Google Scholar
• Choi MK, Jin QR, Jin HE, et al. Effects of tetraalkylammonium compounds with different affinities for organic cation transporters on the pharmacokinetics of metformin. Biopharm Drug Dispos. 2007;28(9):501–510. doi:10.1002/(ISSN)1099-081X17876861
   PubMed Web of Science ®Google Scholar
• Wright SH. Role of organic cation transporters in the renal handling of therapeutic agents and xenobiotics. Toxicol Appl Pharmacol. 2005;204(3):309–319. doi:10.1016/j.taap.2004.10.02115845420
   PubMed Web of Science ®Google Scholar
• Jonker JW, Schinkel AH. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther. 2004;308(1):2–9. doi:10.1124/jpet.103.05329814576340
   PubMed Web of Science ®Google Scholar
• Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;3:e02242. doi:10.7554/eLife.0224224843020
   PubMed Web of Science ®Google Scholar
• Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542. doi:10.1038/nature1327024847880
   PubMed Web of Science ®Google Scholar
• Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174. doi:10.1172/JCI1350511602624
   PubMed Web of Science ®Google Scholar
• Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(3):607–614.10839993
   PubMedGoogle Scholar
• Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res. 2008;1(5):369–375. doi:10.1158/1940-6207.CAPR-08-0081
   PubMed Web of Science ®Google Scholar
• Todd JN, Florez JC. An update on the pharmacogenomics of metformin: progress, problems and potential. Pharmacogenomics. 2014;15(4):529–539. doi:10.2217/pgs.14.2124624919
   PubMed Web of Science ®Google Scholar
• Schäfer G. Site-specific uncoupling and inhibition of oxidative phosphorylation by biguanides. II. Biochim Biophys Acta. 1969;172(2):334–337.4304727
   PubMedGoogle Scholar
• El-Mir M-Y, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biochem Physiol. 2000;275(1):223–228.
   Google Scholar
• Scotland S, Saland E, Skuli N, et al. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia. 2013;27(11):2129. doi:10.1038/leu.2013.10723568147
   PubMed Web of Science ®Google Scholar
• Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol. 2008;233(2):203–210. doi:10.1016/j.taap.2008.08.01318817800
   PubMed Web of Science ®Google Scholar
• Guigas B, Detaille D, Chauvin C, et al. Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study. Biochem J. 2004;382(3):877–884. doi:10.1042/BJ2004088515175014
   PubMedGoogle Scholar
• Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle. 2011;10(23):4047–4064. doi:10.4161/cc.10.23.1815122134189
   PubMed Web of Science ®Google Scholar
• Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev. 2009;89(3):1025–1078. doi:10.1152/physrev.00011.200819584320
   PubMed Web of Science ®Google Scholar
• Carling D. AMPK signalling in health and disease. Curr Opin Cell Biol. 2017;45:31–37. doi:10.1016/j.ceb.2017.01.00528232179
   PubMed Web of Science ®Google Scholar
• Huang X, Wullschleger S, Shpiro N, et al. Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412(2):211–221. doi:10.1042/BJ2008055718387000
   PubMed Web of Science ®Google Scholar
• Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142(2):164–175. doi:10.1016/j.pharmthera.2013.12.00424333502
   PubMed Web of Science ®Google Scholar
• Oh BY, Park YA, Huh JW, et al. Metformin enhances the response to radiotherapy in diabetic patients with rectal cancer. J Cancer Res Clin Oncol. 2016;142(6):1377–1385. doi:10.1007/s00432-016-2148-x27011019
   PubMed Web of Science ®Google Scholar
• Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355–2369. doi:10.1172/jci4067120577053
   PubMed Web of Science ®Google Scholar
• Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390–401. doi:10.1016/j.cmet.2010.03.01420444419
   PubMed Web of Science ®Google Scholar
• Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science (New York, NY). 2005;310(5754):1642–1646. doi:10.1126/science.1120781
   Google Scholar
• Zannella VE, Dal Pra A, Muaddi H, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19(24):6741–6750. doi:10.1158/1078-0432.ccr-13-178724141625
   PubMed Web of Science ®Google Scholar
• Storozhuk Y, Hopmans SN, Sanli T, et al. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br J Cancer. 2013;108(10):2021–2032. doi:10.1038/bjc.2013.18723632475
   PubMed Web of Science ®Google Scholar
• Song CW, Lee H, Dings RP, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012;2:362. doi:10.1038/srep0036222500211
   PubMed Web of Science ®Google Scholar
• Zhang T, Zhang L, Zhang T, et al. Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo. Radiat Res. 2014;181(6):641–649. doi:10.1667/rr13561.124844651
   PubMed Web of Science ®Google Scholar
• Lee M-S, Hsu -C-C, Wahlqvist ML, Tsai H-N, Chang Y-H, Huang Y-C. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11(1):20. doi:10.1186/1471-2407-11-2021241523
   PubMed Web of Science ®Google Scholar
• Decensi A, Puntoni M, Goodwin P, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res. 2010;3(11):1451–1461. doi:10.1158/1940-6207.capr-10-0157
   PubMed Web of Science ®Google Scholar
• Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33(2):322–326. doi:10.2337/dc09-138019918015
   PubMed Web of Science ®Google Scholar
• Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766–1777. doi:10.1007/s00125-009-1440-619572116
   PubMed Web of Science ®Google Scholar
• Soranna D, Scotti L, Zambon A, et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist. 2012;17(6):813–822. doi:10.1634/theoncologist.2011-046222643536
   PubMed Web of Science ®Google Scholar
• Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012;7(3):e33411. doi:10.1371/journal.pone.003341122448244
   PubMed Web of Science ®Google Scholar
• Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. The Lancet Oncol. 2016;17(4):475–483. doi:10.1016/s1470-2045(15)00565-326947328
   PubMed Web of Science ®Google Scholar
• Joshua AM, Zannella VE, Downes MR, et al. A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis. 2014;17(3):252–258. doi:10.1038/pcan.2014.2024861559
   PubMed Web of Science ®Google Scholar
• Campagnoli C, Pasanisi P, Abba C, et al. Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study. Clin Breast Cancer. 2012;12(3):175–182. doi:10.1016/j.clbc.2012.03.00422607767
   PubMed Web of Science ®Google Scholar
• Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E. Sulphonylureas and cancer: a case–control study. Acta Diabetol. 2009;46(4):279. doi:10.1007/s00592-008-0083-219082520
   PubMed Web of Science ®Google Scholar
• Home P, Kahn S, Jones N, Noronha D, Beck-Nielsen H, Viberti G. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia. 2010;53(9):1838–1845. doi:10.1007/s00125-010-1804-y20532476
   PubMed Web of Science ®Google Scholar
• Baur DM, Klotsche J, Hamnvik O-PR, et al. Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism. 2011;60(10):1363–1371. doi:10.1016/j.metabol.2010.09.01221081242
   PubMed Web of Science ®Google Scholar
• Li D, Yeung S-CJ, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482–488. doi:10.1053/j.gastro.2009.04.01319375425
   PubMed Web of Science ®Google Scholar
• Berstein LM, Boyarkina MP, Tsyrlina EV, Turkevich EA, Semiglazov VF. More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin. Med Oncol. 2011;28(4):1260–1263. doi:10.1007/s12032-010-9572-620490716
   PubMed Web of Science ®Google Scholar
• Rieken M, Kluth LA, Xylinas E, et al. Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancer. World J Urol. 2014;32(4):999–1005. doi:10.1007/s00345-013-1171-724062093
   PubMed Web of Science ®Google Scholar
• Spratt DE, Zhang C, Zumsteg ZS, Pei X, Zhang Z, Zelefsky MJ. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol. 2013;63(4):709–716. doi:10.1016/j.eururo.2012.12.00423287698
   PubMed Web of Science ®Google Scholar
• Margel D, Urbach DR, Lipscombe LL, et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol. 2013;31(25):3069–3075. doi:10.1200/JCO.2012.46.704323918942
   PubMed Web of Science ®Google Scholar
• Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32(9):1620–1625. doi:10.2337/dc08-217519564453
   PubMed Web of Science ®Google Scholar
• Monami M, Colombi C, Balzi D, et al. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2011;34(1):129–131. doi:10.2337/dc10-128720980415
   PubMed Web of Science ®Google Scholar
• Bowker SL, Yasui Y, Veugelers P, Johnson JA. Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia. 2010;53(8):1631–1637. doi:10.1007/s00125-010-1750-820407744
   PubMed Web of Science ®Google Scholar
• Bo S, Ciccone G, Rosato R, et al. Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients. Diabetes Obes Metab. 2012;14(1):23–29. doi:10.1111/j.1463-1326.2011.01480.x21812892
   PubMed Web of Science ®Google Scholar
• Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ (Clinical Research Ed.). 2005;330(7503):1304–1305. doi:10.1136/bmj.38415.708634.F7
   PubMed Web of Science ®Google Scholar
• Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27(12):2184–2195. doi:10.1093/annonc/mdw41027681864
   PubMed Web of Science ®Google Scholar
• Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res. 2010;3(9):1077–1083. doi:10.1158/1940-6207.capr-10-0186
   PubMed Web of Science ®Google Scholar
• Garrett CR, Hassabo HM, Bhadkamkar NA, et al. Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br J Cancer. 2012;106(8):1374–1378. doi:10.1038/bjc.2012.7122421948
   PubMed Web of Science ®Google Scholar
• Oliveria SA, Koro CE, Ulcickas Yood M, Sowell M. Cancer incidence among patients treated with antidiabetic pharmacotherapy. Diabetes Metab Syndr. 2008;2(1):47–57. doi:10.1016/j.dsx.2007.11.002
   Google Scholar
• Ruiter R, Visser LE, van Herk-Sukel MP, et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care. 2012;35(1):119–124. doi:10.2337/dc11-085722100960
   PubMed Web of Science ®Google Scholar
• Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33(6):1304–1308. doi:10.2337/dc09-179120299480
   PubMed Web of Science ®Google Scholar
• Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297–3302. doi:10.1200/jco.2009.19.641019487376
   PubMed Web of Science ®Google Scholar
• Zhang Y, Storr SJ, Johnson K, et al. Involvement of metformin and AMPK in the radioresponse and prognosis of luminal versus basal-like breast cancer treated with radiotherapy. Oncotarget. 2014;5(24):12936–12949. doi:10.18632/oncotarget.268325427448
   PubMedGoogle Scholar
• Kim EH, Kim MS, Cho CK, Jung WG, Jeong YK, Jeong JH. Low and high linear energy transfer radiation sensitization of HCC cells by metformin. J Radiat Res. 2014;55(3):432–442. doi:10.1093/jrr/rrt13124375278
   PubMed Web of Science ®Google Scholar
• Aldea MD, Petrushev B, Soritau O, et al. Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells. J BUON. 2014;19(2):502–511.24965413
   PubMed Web of Science ®Google Scholar
• Haugrud AB, Zhuang Y, Coppock JD, Miskimins WK. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat. 2014;147(3):539–550. doi:10.1007/s10549-014-3128-y25212175
   PubMed Web of Science ®Google Scholar
• Skinner HD, McCurdy MR, Echeverria AE, et al. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol. 2013;52(5):1002–1009. doi:10.3109/0284186x.2012.71809622950385
   PubMed Web of Science ®Google Scholar
• Baskar R, Dai J, Wenlong N, Yeo R, Yeoh K-W. Biological response of cancer cells to radiation treatment. Front Mol Biosci. 2014;1:24. doi:10.3389/fmolb.2014.0002425988165
   PubMed Web of Science ®Google Scholar
• Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71(9):3196–3201. doi:10.1158/0008-5472.can-10-347121415163
   PubMed Web of Science ®Google Scholar