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Metformin as Adjuvant Therapy in Ovarian and Endometrial Cancers

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Focus on Gynecologic Malignancies

Part of the book series: Energy Balance and Cancer ((EBAC,volume 13))

Abstract

Obesity has been linked with increased risk for and worse outcomes from cancer, including gynecologic cancers. Metformin (1,1-dimethylbiguanide) is a biguanide anti-hyperglycemic widely used for the treatment of type 2 diabetes. Epidemiologic studies suggest metformin both lowers cancer risk and improves cancer outcomes in diabetic patients when compared to those treated with other anti-diabetic medications. This epidemiologic evidence prompted pre-clinical investigation of the effects of metformin in cancer. In vitro and in vivo data find that metformin possesses anti-cancer effects through both indirect and direct effects on tumor growth. Indirect effects are likely due to inhibition of hepatic gluconeogenesis, resulting in reduced circulating glucose and insulin levels, which may decrease growth factor-stimulated tumor growth. Metformin may directly affect tumor growth through inhibition of mitochondrial complex 1 and activation of adenosine monophosphate-activated protein kinase (AMPK), resulting in the regulation of multiple downstream signaling pathways that control cell proliferation and metabolism, including inhibition of the mammalian target of rapamycin (mTOR) pathway as well as decreased fatty acid and lipid sythesis.

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References

  1. Inzucchi SE, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577–96.

    Article  CAS  PubMed  Google Scholar 

  2. Quinn BJ, et al. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab. 2013;24(9):469–80.

    Article  CAS  PubMed  Google Scholar 

  3. Knowler WC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.

    Article  CAS  PubMed  Google Scholar 

  4. Dronavalli S, Ehrmann DA. Pharmacologic therapy of polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):244–54.

    Article  PubMed  Google Scholar 

  5. Decensi A, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3(11):1451–61.

    Article  CAS  Google Scholar 

  6. Evans JM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bowker SL, et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29(2):254–8.

    Article  PubMed  Google Scholar 

  8. Libby G, et al. 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):1620–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2012;2(9):778–90.

    Article  CAS  PubMed  Google Scholar 

  10. Bonanni B, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012;30(21):2593–600.

    Article  CAS  PubMed  Google Scholar 

  11. Esteva FJ, et al. Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor-positive metastatic breast cancer. Cancer Chemother Pharmacol. 2013;71(1):63–72.

    Article  CAS  PubMed  Google Scholar 

  12. Hosono K, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 2010;3(9):1077–83.

    Article  CAS  Google Scholar 

  13. MacKenzie MJ, et al. A phase I study of temsirolimus and metformin in advanced solid tumours. Investig New Drugs. 2012;30(2):647–52.

    Article  CAS  Google Scholar 

  14. Nobes JP, et al. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int. 2012;109(10):1495–502.

    Article  CAS  PubMed  Google Scholar 

  15. He X, et al. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Ann Oncol. 2012;23(7):1771–80.

    Article  CAS  PubMed  Google Scholar 

  16. He XX, et al. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011;22(12):2640–5.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137(1):25–33.

    Article  CAS  PubMed  Google Scholar 

  18. Collier CA, et al. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab. 2006;291(1):E182–9.

    Article  CAS  PubMed  Google Scholar 

  19. Miller RA, et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494(7436):256–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9.

    Article  CAS  PubMed  Google Scholar 

  21. Shin NR, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63(5):727–35.

    Article  CAS  PubMed  Google Scholar 

  22. Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10(3):143–56.

    Article  CAS  PubMed  Google Scholar 

  23. Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annu Rev Med. 2015;66:17–29.

    Article  CAS  PubMed  Google Scholar 

  24. Wheaton WW, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. elife. 2014;3:e02242.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu X, et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci U S A. 2014;111(4):E435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pierotti MA, et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2013;32(12):1475–87.

    Article  CAS  PubMed  Google Scholar 

  27. Ben Sahra I, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71(13):4366–72.

    Article  CAS  PubMed  Google Scholar 

  28. Gou S, et al. Low concentrations of metformin selectively inhibit CD133(+) cell proliferation in pancreatic cancer and have anticancer action. PLoS One. 2013;8(5):e63969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gunter MJ, et al. A prospective evaluation of insulin and insulin-like growth factor-i as risk factors for endometrial cancer. Cancer Epidemiol Biomark Prev. 2008;17(4):921–9.

    Article  CAS  Google Scholar 

  30. Berns EM, et al. Receptors for hormones and growth factors and (onco)-gene amplification in human ovarian cancer. Int J Cancer. 1992;52(2):218–24.

    Article  CAS  PubMed  Google Scholar 

  31. van Dam PA, et al. Expression of c-erbB-2, c-myc, and c-ras oncoproteins, insulin-like growth factor receptor I, and epidermal growth factor receptor in ovarian carcinoma. J Clin Pathol. 1994;47(10):914–9.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Brokaw J, et al. IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors. 2007;25(5):346–54.

    Article  CAS  PubMed  Google Scholar 

  33. Spentzos D, et al. IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. Endocr Relat Cancer. 2007;14(3):781–90.

    Article  CAS  PubMed  Google Scholar 

  34. McCampbell AS, et al. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res. 2006;12(21):6373–8.

    Article  CAS  PubMed  Google Scholar 

  35. Dedes KJ, et al. Emerging therapeutic targets in endometrial cancer. Nat Rev Clin Oncol. 2011;8(5):261–71.

    Article  CAS  PubMed  Google Scholar 

  36. Salvesen HB, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci U S A. 2009;106(12):4834–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cheung LW, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1(2):170–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kandoth C, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

    Article  PubMed  CAS  Google Scholar 

  39. Sun M, et al. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol. 2001;159(2):431–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bellacosa A, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995;64(4):280–5.

    Article  CAS  PubMed  Google Scholar 

  41. Shayesteh L, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999;21(1):99–102.

    Article  CAS  PubMed  Google Scholar 

  42. Levine DA, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005;11(8):2875–8.

    Article  CAS  PubMed  Google Scholar 

  43. Philp AJ, et al. The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 2001;61(20):7426–9.

    CAS  PubMed  Google Scholar 

  44. Saito M, et al. Allelic imbalance and mutations of the PTEN gene in ovarian cancer. Int J Cancer. 2000;85(2):160–5.

    Article  CAS  PubMed  Google Scholar 

  45. Hursting SD, et al. Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. Best Pract Res Clin Endocrinol Metab. 2008;22(4):659–69.

    Article  CAS  PubMed  Google Scholar 

  46. Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007;13(6):252–9.

    Article  CAS  PubMed  Google Scholar 

  47. Wysocki PJ, Wierusz-Wysocka B. Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin. Expert Rev Mol Diagn. 2010;10(4):509–19.

    Article  CAS  PubMed  Google Scholar 

  48. Gonzalez-Angulo AM, Meric-Bernstam F. Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res. 2010;16(6):1695–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jiang W, Zhu Z, Thompson HJ. Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver. Cancer Res. 2008;68(13):5492–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Moore T, et al. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila). 2008;1(1):65–76.

    Article  CAS  Google Scholar 

  51. Wang DS, et al. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302(2):510–5.

    Article  CAS  PubMed  Google Scholar 

  52. Kimura N, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005;20(5):379–86.

    Article  CAS  PubMed  Google Scholar 

  53. Kimura N, Okuda M, Inui K. Metformin transport by renal basolateral organic cation transporter hOCT2. Pharm Res. 2005;22(2):255–9.

    Article  CAS  PubMed  Google Scholar 

  54. Terada T, et al. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006;23(8):1696–701.

    Article  CAS  PubMed  Google Scholar 

  55. Masuda S, et al. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol. 2006;17(8):2127–35.

    Article  CAS  PubMed  Google Scholar 

  56. Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos. 2007;35(10):1956–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Han, T., Proctor W, Costales C, Everett R, Thakker D. The role of the organic cation transporter 1 (OCT1) and plasma membrane monoamine transporter (PMAT) in metformin apical uptake in Caco-2 cells. Proceedings of the annual meeting of the American association of pharmaceutical scientists, 2011.

    Google Scholar 

  58. Winter TN, Elmquist WF, Fairbanks CA. OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm. 2011;8(1):133–42.

    Article  CAS  PubMed  Google Scholar 

  59. Emami Riedmaier A, et al. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci. 2013;34(2):126–35.

    Article  PubMed  CAS  Google Scholar 

  60. Schaeffeler E, et al. DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma. Genome Med. 2011;3(12):82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cai H, et al. Cation-selective transporters are critical to the AMPK-mediated antiproliferative effects of metformin in human breast cancer cells. Int J Cancer. 2016;138(9):2281–92.

    Article  CAS  PubMed  Google Scholar 

  62. Shu Y, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83(2):273–80.

    Article  CAS  PubMed  Google Scholar 

  63. Shu Y, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117(5):1422–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nies AT, et al. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol. 2011;201:105–67.

    Article  CAS  Google Scholar 

  65. Tzvetkov MV, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009;86(3):299–306.

    Article  CAS  PubMed  Google Scholar 

  66. McGuinness ME, Talbert RL. Phenformin-induced lactic acidosis: a forgotten adverse drug reaction. Ann Pharmacother. 1993;27(10):1183–7.

    Article  CAS  PubMed  Google Scholar 

  67. Owen MR, 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(Pt 3):607–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Searle GL, Siperstein MD. Lactic acidosis associated with phenformin therapy. Evidence that inhibited lactate oxidation is the causative factor. Diabetes. 1975;24(8):741–5.

    Article  CAS  PubMed  Google Scholar 

  69. Williams RH, Steiner DF. Summarization of studies relative to the mechanism of phenethylbiguanide hypoglycemia. Metabolism. 1959;8(4 Pt 2):548–52.

    CAS  PubMed  Google Scholar 

  70. Stumvoll M, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550–4.

    Article  CAS  PubMed  Google Scholar 

  71. Graham GG, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81–98.

    Article  CAS  PubMed  Google Scholar 

  72. Huang X, et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412(2):211–21.

    Article  CAS  PubMed  Google Scholar 

  73. Appleyard MV, et al. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer. 2012;106(6):1117–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lea MA, et al. Addition of 2-deoxyglucose enhances growth inhibition but reverses acidification in colon cancer cells treated with phenformin. Anticancer Res. 2011;31(2):421–6.

    CAS  PubMed  Google Scholar 

  75. Caraci F, et al. Effects of phenformin on the proliferation of human tumor cell lines. Life Sci. 2003;74(5):643–50.

    Article  CAS  PubMed  Google Scholar 

  76. Orecchioni S, et al. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J Cancer. 2015;136(6):E534–44.

    Article  CAS  PubMed  Google Scholar 

  77. Jiang W, et al. Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma. Oncotarget. 2016;7(35):56456–70.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Dilman VM, Anisimov VN. Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice. Gerontology. 1980;26(5):241–6.

    Article  CAS  PubMed  Google Scholar 

  79. Shackelford DB, et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 2013;23(2):143–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Aoki M, et al. Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation. Am J Physiol Renal Physiol. 2008;295(1):F165–70.

    Article  CAS  PubMed  Google Scholar 

  81. Segal ED, et al. Relevance of the OCT1 transporter to the antineoplastic effect of biguanides. Biochem Biophys Res Commun. 2011;414(4):694–9.

    Article  CAS  PubMed  Google Scholar 

  82. Iczkowski KA, et al. Trials of new germ cell immunohistochemical stains in 93 extragonadal and metastatic germ cell tumors. Hum Pathol. 2008;39(2):275–81.

    Article  CAS  PubMed  Google Scholar 

  83. Hilgendorf C, et al. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab Dispos. 2007;35(8):1333–40.

    Article  CAS  PubMed  Google Scholar 

  84. Zhang L, et al. NT1014, a novel biguanide, inhibits ovarian cancer growth in vitro and in vivo. J Hematol Oncol. 2016;9(1):91.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Cantrell LA, et al. Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy. Gynecol Oncol. 2010;116(1):92–8.

    Article  CAS  PubMed  Google Scholar 

  86. Iglesias DA, et al. Another surprise from metformin: novel mechanism of action via K-Ras influences endometrial cancer response to therapy. Mol Cancer Ther. 2013;12(12):2847–56.

    Article  CAS  PubMed  Google Scholar 

  87. Sarfstein R, et al. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. PLoS One. 2013;8(4):e61537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Erdemoglu E, et al. Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):195–9.

    Article  CAS  PubMed  Google Scholar 

  89. Tan BK, et al. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab. 2011;96(3):808–16.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang Q, et al. Chemopreventive effects of metformin on obesity-associated endometrial proliferation. Am J Obstet Gynecol. 2013;209(1):24 e1–24 e12.

    Article  CAS  Google Scholar 

  91. Hanna RK, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol. 2012;125(2):458–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dong L, et al. Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J Obstet Gynaecol Res. 2012;38(8):1077–85.

    Article  CAS  PubMed  Google Scholar 

  93. Zhang Z, et al. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011;21(2):213–21.

    Article  PubMed  Google Scholar 

  94. Mu N, Wang Y, Xue F. Metformin: a potential novel endometrial cancer therapy. Int J Gynecol Cancer. 2012;22(2):181.

    Article  PubMed  Google Scholar 

  95. Wang Y, et al. Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway. Oncotarget. 2016;7(9):10363–72.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wu B, et al. Metformin inhibits the development and metastasis of ovarian cancer. Oncol Rep. 2012;28(3):903–8.

    Article  CAS  PubMed  Google Scholar 

  97. Yasmeen A, et al. Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol. 2011;121(3):492–8.

    Article  CAS  PubMed  Google Scholar 

  98. Liao H, et al. Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through the mTOR signaling pathway. Oncol Rep. 2012;27(6):1873–8.

    CAS  PubMed  Google Scholar 

  99. Rattan R, et al. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2011;15(1):166–78.

    Article  CAS  PubMed  Google Scholar 

  100. Rattan R, et al. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13(5):483–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Li C, et al. LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells. Int J Gynecol Cancer. 2012;22(1):15–22.

    Article  PubMed  Google Scholar 

  102. Gwak H, et al. Metformin induces degradation of cyclin D1 via AMPK/GSK3beta axis in ovarian cancer. Mol Carcinog. 2017;56(2):349–58.

    Article  CAS  PubMed  Google Scholar 

  103. Patel S, Singh N, Kumar L. Evaluation of effects of metformin in primary ovarian cancer cells. Asian Pac J Cancer Prev. 2015;16(16):6973–9.

    Article  PubMed  Google Scholar 

  104. Chan DK, Miskimins WK. Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures. J Ovarian Res. 2012;5(1):19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Erices R, et al. Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells. Reprod Sci. 2013;20(12):1433–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Shank JJ, et al. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol. 2012;127(2):390–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gotlieb WH, et al. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol. 2008;110(2):246–50.

    Article  CAS  PubMed  Google Scholar 

  108. Hijaz M, et al. Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer. Gynecol Oncol. 2016;142(2):323–31.

    Article  CAS  PubMed  Google Scholar 

  109. Algire C, et al. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer. 2008;15(3):833–9.

    Article  CAS  PubMed  Google Scholar 

  110. Phoenix KN, et al. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res Treat. 2010;123(2):333–44.

    Article  CAS  PubMed  Google Scholar 

  111. Jackson A, Zhong Y, Zhou C, Kilgore J, Makowski L, Gehrig P, Bae-Jump V. Metformin had increased efficacy under obese conditions in a novel genetically engineered mouse model of serous ovarian cancer. Annual meeting of the society of gynecologic oncology annual meeting, 2014.

    Google Scholar 

  112. Makowski L, et al. Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer. Gynecol Oncol. 2014;133(1):90–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wysham, W., Zhong, Y, Dickens, HK, Malloy, KM, Han, X, Guo, H, Zhou, C, Makowski, L, Bae-Jump, VL. Increased efficacy of metformin corresponds to differential metabolic effects in the ovarian tumors from obese versus lean mice. 47th annual meeting of the society of gynecologic oncology, Mar 2016, San Diego, CA.

    Google Scholar 

  114. Litchfield LM, et al. Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer. Oncotarget. 2015;6(27):23548–60.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Zhang Q, et al. CGRRF1 as a novel biomarker of tissue response to metformin in the context of obesity. Gynecol Oncol. 2014;133(1):83–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.

    Article  PubMed  Google Scholar 

  117. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  118. Ko EM, et al. The complex triad of obesity, diabetes and race in type I and II endometrial cancers: prevalence and prognostic significance. Gynecol Oncol. 2014;133(1):28–32.

    Article  PubMed  Google Scholar 

  119. Setiawan VW, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31(20):2607–18.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Schmandt RE, et al. Understanding obesity and endometrial cancer risk: opportunities for prevention. Am J Obstet Gynecol. 2011;205(6):518–25.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Secord AA, et al. Body mass index and mortality in endometrial cancer: a systematic review and meta-analysis. Gynecol Oncol. 2016;140(1):184–90.

    Article  PubMed  Google Scholar 

  122. Renehan AG, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78.

    Article  PubMed  Google Scholar 

  123. Chia VM, et al. Obesity, diabetes, and other factors in relation to survival after endometrial cancer diagnosis. Int J Gynecol Cancer. 2007;17(2):441–6.

    Article  CAS  PubMed  Google Scholar 

  124. Calle EE, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38.

    Article  PubMed  Google Scholar 

  125. Steiner E, et al. Diabetes mellitus is a multivariate independent prognostic factor in endometrial carcinoma: a clinicopathologic study on 313 patients. Eur J Gynaecol Oncol. 2007;28(2):95–7.

    CAS  PubMed  Google Scholar 

  126. Arem H, et al. Prediagnosis body mass index, physical activity, and mortality in endometrial cancer patients. J Natl Cancer Inst. 2013;105(5):342–9.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Ward KK, et al. Cardiovascular disease is the leading cause of death among endometrial cancer patients. Gynecol Oncol. 2012;126(2):176–9.

    Article  PubMed  Google Scholar 

  128. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10–7.

    Article  CAS  PubMed  Google Scholar 

  129. Currie CJ, et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299–304.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Nevadunsky NS, et al. Metformin use and endometrial cancer survival. Gynecol Oncol. 2014;132(1):236–40.

    Article  CAS  PubMed  Google Scholar 

  131. Ko EM, et al. Metformin is associated with improved survival in endometrial cancer. Gynecol Oncol. 2014;132(2):438–42.

    Article  CAS  PubMed  Google Scholar 

  132. Becker C, et al. Metformin and the risk of endometrial cancer: a case-control analysis. Gynecol Oncol. 2013;129(3):565–9.

    Article  CAS  PubMed  Google Scholar 

  133. Ko E, Stürmer T, Hong JL, Castillo WC, Bae-Jump VL, Jonsson Funk M. Metformin and the risk of endometrial cancer: a population-based cohort study. Annual meeting of the society of gynecologic oncology annual meeting, 2014.

    Google Scholar 

  134. cancer.org, http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-survival-rates. 2014.

  135. Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol. 2006;20(2):207–25.

    Article  CAS  PubMed  Google Scholar 

  136. Markmann S, Gerber B, Briese V. Prognostic value of Ca 125 levels during primary therapy. Anticancer Res. 2007;27(4a):1837–9.

    PubMed  Google Scholar 

  137. Protani MM, Nagle CM, Webb PM. Obesity and ovarian cancer survival: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2012;5(7):901–10.

    Article  Google Scholar 

  138. Yang HS, et al. Effect of obesity on survival of women with epithelial ovarian cancer: a systematic review and meta-analysis of observational studies. Int J Gynecol Cancer. 2011;21(9):1525–32.

    Article  PubMed  Google Scholar 

  139. Olsen CM, et al. Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer. 2007;43(4):690–709.

    Article  PubMed  Google Scholar 

  140. Lubin F, et al. Body mass index at age 18 years and during adult life and ovarian cancer risk. Am J Epidemiol. 2003;157(2):113–20.

    Article  CAS  PubMed  Google Scholar 

  141. Engeland A, et al. Height and body mass index in relation to total mortality. Epidemiology. 2003;14(3):293–9.

    PubMed  Google Scholar 

  142. Bodmer M, et al. Use of metformin and the risk of ovarian cancer: a case-control analysis. Gynecol Oncol. 2011;123(2):200–4.

    Article  CAS  PubMed  Google Scholar 

  143. Romero IL, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61–7.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Kumar S, et al. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer. 2013;119(3):555–62.

    Article  CAS  PubMed  Google Scholar 

  145. Brenner DE, Hawk E. Trials and tribulations of interrogating biomarkers to define efficacy of cancer risk reductive interventions. Cancer Prev Res (Phila). 2013;6(2):71–3.

    Article  Google Scholar 

  146. Fabian CJ, et al. Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator. Clin Cancer Res. 2004;10(16):5403–17.

    Article  CAS  PubMed  Google Scholar 

  147. Patel KR, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70(19):7392–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Heymach JV, et al. Effect of low-fat diets on plasma levels of NF-kappaB-regulated inflammatory cytokines and angiogenic factors in men with prostate cancer. Cancer Prev Res (Phila). 2011;4(10):1590–8.

    Article  CAS  Google Scholar 

  149. Simoneau AR, et al. Alpha-difluoromethylornithine and polyamine levels in the human prostate: results of a phase IIa trial. J Natl Cancer Inst. 2001;93(1):57–9.

    Article  CAS  PubMed  Google Scholar 

  150. Hadad S, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat. 2011;128(3):783–94.

    Article  CAS  PubMed  Google Scholar 

  151. Bullwinkel J, et al. Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol. 2006;206(3):624–35.

    Article  CAS  PubMed  Google Scholar 

  152. Joshua AM, et al. A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis. 2014;17(3):252–8.

    Article  CAS  PubMed  Google Scholar 

  153. Laskov I, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol. 2014;134(3):607–14.

    Article  CAS  PubMed  Google Scholar 

  154. Schuler KM, et al. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med. 2015;4(2):161–73.

    Article  CAS  PubMed  Google Scholar 

  155. Sivalingam V, et al. A presurgical window-of-opportunity study of metformin in obesity-driven endometrial cancer. Lancet. 2015;385(Suppl 1):S90.

    Article  PubMed  Google Scholar 

  156. Sivalingam VN, et al. Measuring the biological effect of presurgical metformin treatment in endometrial cancer. Br J Cancer. 2016;114(3):281–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Soliman PT, Broaddus RB, Westin S, Iglesias D, Munsell MR, Schmandt R et al. Phase 0 study: prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer. Society of gynecologic oncologists annual meeting on women’s cancer, society of gynecologic oncologists, 2013; p S15.

    Google Scholar 

  158. Mitsuhashi A, et al. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer. 2014;120(19):2986–95.

    Article  CAS  PubMed  Google Scholar 

  159. Staley, S., Roque, DR, Schuler, KM, Rambally, BS, Sampey, B, Everett, Thakker, D, Gehrig, PA, O’Connor, S, Makowski, S, VL Bae-Jump Molecular and metabolic differences of treatment responders versus non-responders in a phase 0 clinical trial of metformin in endometrial cancer. 47th annual meeting of the society of gynecologic oncology, Mar 2016, San Diego, CA.

    Google Scholar 

  160. Soliman PT, et al. Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: a window of opportunity study. Gynecol Oncol. 2016;143(3):466–71.

    Article  CAS  PubMed  Google Scholar 

  161. Khawaja MR, et al. Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. Cancer Chemother Pharmacol. 2016;77(5):973–7.

    Article  CAS  PubMed  Google Scholar 

  162. Miranda VC, et al. Phase 2 trial of metformin combined with 5-fluorouracil in patients with refractory metastatic colorectal cancer. Clin Colorectal Cancer. 2016;15(4):321–328.e1.

    Article  PubMed  Google Scholar 

  163. Braghiroli MI, et al. Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas. ECancerMedicalScience. 2015;9:563.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Goodwin PJ, et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015;107(3):djv006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Mitsuhashi A, et al. Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer. Ann Oncol. 2016;27(2):262–6.

    Article  CAS  PubMed  Google Scholar 

  166. Soliman PT, Westin SN, Iglesias DA, Munsell MF, Slomovitz BM, Lu KH, Coleman RL. Phase II study of everolimus, letrozole, and metformin in women with advanced/recurrent endometrial cancer. J Clin Oncol. 2016;34:5506.

    Article  Google Scholar 

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Authors and Affiliations

  1. University of North Carolina School of Medicine, 101 Manning Drive, First Floor, Chapel Hill, NC, 27514, USA

    Leslie H. Clark M.D. & Victoria L. Bae-Jump M.D., Ph.D.

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  1. Leslie H. Clark M.D.
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  2. Victoria L. Bae-Jump M.D., Ph.D.
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Correspondence to Victoria L. Bae-Jump M.D., Ph.D. .

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  1. Center for Science, Health and Society, Case Western Reserve University, Cleveland, Ohio, USA

    Nathan A. Berger

  2. Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA

    Ann H. Klopp

  3. Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, Texas, USA

    Karen H. Lu

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Clark, L.H., Bae-Jump, V.L. (2018). Metformin as Adjuvant Therapy in Ovarian and Endometrial Cancers. In: Berger, N., Klopp, A., Lu, K. (eds) Focus on Gynecologic Malignancies. Energy Balance and Cancer, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-63483-8_16

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