1932

Abstract

Patients with diabetes mellitus are at increased risk of cancer development. Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus. Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent. Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism. This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence.

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2015-01-14
2024-06-19
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Literature Cited

  1. Wild S, Roglic G, Green A. 1.  et al. 2004. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–53 [Google Scholar]
  2. 2. American Diabetes Association 2013. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 36:1033–46 [Google Scholar]
  3. Saltiel AR, Kahn CR. 3.  2001. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806 [Google Scholar]
  4. Spellman CW.4.  2010. Pathophysiology of type 2 diabetes: targeting islet cell dysfunction. J. Am. Osteopath. Assoc. 110:S2–7 [Google Scholar]
  5. Vigneri P, Frasca F, Sciacca L. 5.  et al. 2009. Diabetes and cancer. Endocr. Relat. Cancer 16:1103–23 [Google Scholar]
  6. Barone BB, Yeh HC, Snyder CF. 6.  et al. 2008. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–64 [Google Scholar]
  7. De Bruijn KM, Arends LR, Hansen BE. 7.  et al. 2013. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br. J. Surg. 100:1421–29 [Google Scholar]
  8. Bensimon L, Yin H, Suissa S. 8.  et al. 2014. Type 2 diabetes and the risk of mortality among patients with prostate cancer. Cancer Causes Control 25:329–38 [Google Scholar]
  9. Ma J, Li H, Giovannucci E. 9.  et al. 2008. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 9:1039–47 [Google Scholar]
  10. Giovannucci E, Harlan DM, Archer MC. 10.  et al. 2010. Diabetes and cancer: a consensus report. Diabetes Care 33:1674–85 [Google Scholar]
  11. Frasca F, Pandini G, Sciacca L. 11.  et al. 2008. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch. Physiol. Biochem. 114:23–37 [Google Scholar]
  12. Sachdev D, Yee D. 12.  2007. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol. Cancer Ther. 6:1–12 [Google Scholar]
  13. Nestler JE, Powers LP, Matt DW. 13.  et al. 1991. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 72:83–89 [Google Scholar]
  14. Key T, Appleby P, Barnes I, Reeves G. 14.  2002. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J. Natl. Cancer Inst. 94:606–16 [Google Scholar]
  15. Gonda TA, Tu S, Wang TC. 15.  2009. Chronic inflammation, the tumor microenvironment and carcinogenesis. Cell Cycle 8:2005–13 [Google Scholar]
  16. Nathan DM, Buse JB, Davidson MB. 16.  et al. 2009. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193–203 [Google Scholar]
  17. Viollet B, Guigas B, Sanz Garcia N. 17.  et al. 2012. Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. 122:253–70 [Google Scholar]
  18. El-Mir MY, Nogueira V, Fontaine E. 18.  et al. 2000. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275:223–28 [Google Scholar]
  19. Viollet B, Guigas B, Leclerc J. 19.  et al. 2009. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol. 196:81–98 [Google Scholar]
  20. Vander Heiden MG, Cantley LC, Thompson CB. 20.  2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–33 [Google Scholar]
  21. Levine AJ, Puzio-Kuter AM. 21.  2010. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330:1340–44 [Google Scholar]
  22. Faubert B, Boily G, Izreig S. 22.  et al. 2013. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17:113–24 [Google Scholar]
  23. Wu SB, Wei YH. 23.  2012. AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: implication of the cell survival in mitochondrial diseases. Biochim. Biophys. Acta 1822:233–47 [Google Scholar]
  24. Mehenni H, Gehrig C, Nezu J. 24.  et al. 1998. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am. J. Hum. Genet. 63:1641–50 [Google Scholar]
  25. Kalaany NY, Sabatini DM. 25.  2009. Tumours with PI3K activation are resistant to dietary restriction. Nature 458:725–31 [Google Scholar]
  26. Vander Heiden MG, Plas DR, Rathmell JC. 26.  et al. 2001. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol. Cell. Biol. 21:5899–912 [Google Scholar]
  27. Shackelford DB, Abt E, Gerken L. 27.  et al. 2013. LKB1 inactivation dictates therapeutic response of non–small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143–58 [Google Scholar]
  28. Vazquez-Martin A, Colomer R, Brunet J. 28.  et al. 2008. Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Prolif. 41:59–85 [Google Scholar]
  29. Xiang X, Saha AK, Wen R. 29.  et al. 2004. AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. Biochem. Biophys. Res. Commun. 321:161–67 [Google Scholar]
  30. Bijland S, Mancini SJ, Salt IP. 30.  2013. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin. Sci. 124:491–507 [Google Scholar]
  31. Yu H, Pardoll D, Jove R. 31.  2009. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9:798–809 [Google Scholar]
  32. Hirsch HA, Iliopoulos D, Struhl K. 32.  2013. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl. Acad. Sci. USA 110:972–77 [Google Scholar]
  33. Ersoy C, Kiyici S, Budak F. 33.  et al. 2008. The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabetes Res. Clin. Pract. 81:56–60 [Google Scholar]
  34. Rizos CV, Elisaf MS. 34.  2013. Metformin and cancer. Eur. J. Pharmacol. 705:96–108 [Google Scholar]
  35. Iliopoulos D, Hirsch HA, Struhl K. 35.  2011. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 71:3196–201 [Google Scholar]
  36. Dong L, Zhou Q, Zhang Z. 36.  et al. 2012. Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J. Obstet. Gynaecol. Res. 38:1077–85 [Google Scholar]
  37. Erices R, Bravo ML, Gonzalez P. 37.  et al. 2013. Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells. Reprod. Sci. 20:1433–46 [Google Scholar]
  38. Asensio-Lopez MC, Lax A, Pascual-Figal DA. 38.  et al. 2011. Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system. Free Radic. Biol. Med. 51:1861–71 [Google Scholar]
  39. Chang J, Jung HH, Yang JY. 39.  et al. 2013. Protective effect of metformin against cisplatin-induced ototoxicity in an auditory cell line. J. Assoc. Res. Otolaryngol. 15:149–58 [Google Scholar]
  40. Landman GW, Kleefstra N, van Hateren KJ. 40.  et al. 2010. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33:322–26 [Google Scholar]
  41. Bowker SL, Yasui Y, Veugelers P, Johnson JA. 41.  2010. Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia 53:1631–37 [Google Scholar]
  42. Currie CJ, Poole CD, Jenkins-Jones S. 42.  et al. 2012. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 35:299–304 [Google Scholar]
  43. Franciosi M, Lucisano G, Lapice E. 43.  et al. 2013. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLOS ONE 8:e71583 [Google Scholar]
  44. Jiralerspong S, Palla SL, Giordano SH. 44.  et al. 2009. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol. 27:3297–302 [Google Scholar]
  45. Bayraktar S, Hernadez-Aya LF, Lei X. 45.  et al. 2012. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer 118:1202–11 [Google Scholar]
  46. Hou G, Zhang S, Zhang X. 46.  et al. 2013. Clinical pathological characteristics and prognostic analysis of 1,013 breast cancer patients with diabetes. Breast Cancer Res. Treat. 137:807–16 [Google Scholar]
  47. Chen TM, Lin CC, Huang PT, Wen CF. 47.  2011. Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. J. Gastroenterol. Hepatol. 26:858–65 [Google Scholar]
  48. Romero IL, McCormick A, McEwen KA. 48.  et al. 2012. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet. Gynecol. 119:61–67 [Google Scholar]
  49. Kumar S, Meuter A, Thapa P. 49.  et al. 2013. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer 119:555–62 [Google Scholar]
  50. Nevadunsky NS, Van Arsdale A, Strickler HD. 50.  et al. 2013. Metformin use and endometrial cancer survival. Gynecol. Oncol. 32:236–40 [Google Scholar]
  51. Garrett CR, Hassabo HM, Bhadkamkar NA. 51.  et al. 2012. Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br. J. Cancer 106:1374–78 [Google Scholar]
  52. Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. 52.  2012. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin. Cancer Res. 18:2905–12 [Google Scholar]
  53. Skinner HD, McCurdy MR, Echeverria AE. 53.  et al. 2013. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol. 52:1002–9 [Google Scholar]
  54. Tan BX, Yao WX, Ge J. 54.  et al. 2011. Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer 117:5103–11 [Google Scholar]
  55. Hadad S, Iwamoto T, Jordan L. 55.  et al. 2011. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res. Treat. 128:783–94 [Google Scholar]
  56. Niraula S, Dowling RJ, Ennis M. 56.  et al. 2012. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res. Treat. 135:821–30 [Google Scholar]
  57. Bonanni B, Puntoni M, Cazzaniga M. 57.  et al. 2012. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J. Clin. Oncol. 30:2593–600 [Google Scholar]
  58. Hosono K, Endo H, Takahashi H. 58.  et al. 2010. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev. Res. 3:1077–83 [Google Scholar]
  59. Evans JM, Donnelly LA, Emslie-Smith AM. 59.  et al. 2005. Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–5 [Google Scholar]
  60. Thakkar B, Aronis KN, Vamvini MT. 60.  et al. 2013. Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metab. Clin. Exp. 62:922–34 [Google Scholar]
  61. Zhang P, Li H, Tan X. 61.  et al. 2013. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 37:207–18 [Google Scholar]
  62. Home PD, Kahn SE, Jones NP. 62.  et al. 2010. 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 53:1838–45 [Google Scholar]
  63. Janjetovic K, Vucicevic L, Misirkic M. 63.  et al. 2011. Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur. J. Pharmacol. 651:41–50 [Google Scholar]
  64. Suissa S, Azoulay L. 64.  2012. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35:2665–73 [Google Scholar]
  65. Azoulay L, Dell'Aniello S, Gagnon B. 65.  et al. 2011. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol. Biomark. Prev. 20:337–44 [Google Scholar]
  66. Smiechowski B, Azoulay L, Yin H. 66.  et al. 2013. The use of metformin and colorectal cancer incidence in patients with type II diabetes mellitus. Cancer Epidemiol. Biomark. Prev. 22:1877–83 [Google Scholar]
  67. Smiechowski BB, Azoulay L, Yin H. 67.  et al. 2013. The use of metformin and the incidence of lung cancer in patients with type 2 diabetes. Diabetes Care 36:124–29 [Google Scholar]
  68. Mamtani R, Pfanzelter N, Haynes K. 68.  et al. 2014. Incidence of bladder cancer in patients with type 2 diabetes treated with metformin or sulfonylureas. Diabetes Care 37:1910–17 [Google Scholar]
  69. 69. National Cancer Institute 2014. A phase III randomized trial of metformin versus placebo in early stage breast cancer http://www.cancer.gov/clinicaltrials/search/view?cdrid=669788&version=HealthProfessional. Accessed Jan. 3, 2014 [Google Scholar]
  70. 70. National Cancer Institute 2014. Evaluation of metformin, targeting cancer stem cells for prevention of relapse in gynecologic patients. http://www.cancer.gov/clinicaltrials/search/view?cdrid=732286&version=HealthProfessional. Accessed Jan. 3, 2014
  71. Brose MS, Rebbeck TR, Calzone KA. 71.  et al. 2002. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J. Natl. Cancer Inst. 94:1365–72 [Google Scholar]
  72. Higurashi T, Takahashi H, Endo H. 72.  et al. 2012. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer 12:118 [Google Scholar]
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