Perspectives of metformin use in endometrial cancer and other gynaecological malignancies

References

• Kitson S, Ryan N, MacKintosh ML, et al. Interventions for weight reduction in obesity to improve survival in women with endometrial cancer. Cochrane Database Syst Rev. 2018;2:CD012513.
   PubMedGoogle Scholar
• MacKintosh ML, Crosbie EJ. Prevention strategies in endometrial carcinoma. Curr Oncol Rep. 2018;13:101.
   Google Scholar
• Kerr J, Anderson C, Lippman SM. Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence. Lancet Oncol. 2017;18(8):e457–e471.
   PubMed Web of Science ®Google Scholar
• Fang X, Wei J, He X, et al. Quantitative association between body mass index and the risk of cancer: a global meta-analysis of prospective cohort studies. Int J Cancer. 2018;143(7):1595–1603.
   PubMed Web of Science ®Google Scholar
• Zhang ZH, Su PY, Hao JH, et al. The role of preexisting diabetes mellitus on incidence and mortality of endometrial cancer: a meta-analysis of prospective cohort studies. Int J Gynecol Cancer. 2013;23(2):294–303.
   PubMed Web of Science ®Google Scholar
• Byrne FL, Martin AR, Kosasih M, et al. The role of hyperglycemia in endometrial cancer pathogenesis. Cancers (Basel). 2020;12(5):1191.
   Web of Science ®Google Scholar
• Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(5):748–758.
   PubMed Web of Science ®Google Scholar
• Faghfoori Z, Fazelian S, Shadnoush M, et al. Nutritional management in women with polycystic ovary syndrome: a review study. Diabetes Metab Syndr. 2017;11 Suppl 1 (Suppl 1):S429–S432.
   PubMedGoogle Scholar
• Tzotzas T, Karras SN, Katsiki N. Glucagon-Like peptide-1 (GLP-1) receptor agonists in the treatment of obese women with polycystic ovary syndrome. Curr Vasc Pharmacol. 2017;15(3):218–229.
   PubMed Web of Science ®Google Scholar
• Wang S, Hong X, Tu Z, et al. Angiopoietin-like protein 8: an attractive biomarker for the evaluation of subjects with insulin resistance and related disorders. Diabetes Res Clin Pract. 2017;133:168–177.
   PubMed Web of Science ®Google Scholar
• Anastasi E, Filardi T, Tartaglione S, et al. Linking type 2 diabetes and gynecological cancer: an introductory overview. Clin Chem Lab Med. 2018;56(9):1413–1425.
   PubMed Web of Science ®Google Scholar
• Kaneto H, Kimura T, Obata A, et al. Multifaceted mechanisms of action of metformin which have been unraveled one after another in the long history. IJMS. 2021;22(5):2596.
   Google Scholar
• Pawelczyk L, Spaczynski RZ, Banaszewska B, et al. Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2004;113(2):209–213.
   PubMed Web of Science ®Google Scholar
• Driver C, Bamitale KDS, Kazi A, et al. Cardioprotective effects of metformin. J Cardiovasc Pharmacol. 2018;72(2):121–127.
   PubMed Web of Science ®Google Scholar
• Jones GR, Molloy MP. Metformin, microbiome and protection against colorectal cancer. Dig Dis Sci. 2021;66(5):1409–1414.
   PubMed Web of Science ®Google Scholar
• Tilg H, Adolph TE, Gerner RR, et al. The intestinal microbiota in colorectal cancer. Cancer Cell. 2018;33(6):954–964.
   PubMed Web of Science ®Google Scholar
• Reitz KM, Marroquin OC, Zenati MS, et al. Association between preoperative metformin exposure and postoperative outcomes in adults with type 2 diabetes. JAMA Surg. 2020;155(6):e200416.
   PubMed Web of Science ®Google Scholar
• Zaafar DK, Zaitone SA, Moustafa YM. Role of metformin in suppressing 1,2-dimethylhydrazine-induced Colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation. PLoS One. 2014;9(6):e100562.
   PubMed Web of Science ®Google Scholar
• Ko EM, Walter P, Jackson A, et al. Metformin is associated with improved survival in endometrial cancer. Gynecol Oncol. 2014;132(2):438–442.
   PubMed Web of Science ®Google Scholar
• Ezewuiro O, Grushko TA, Kocherginsky M, et al. Association of metformin use with outcomes in advanced endometrial cancer treated with chemotherapy. PLoS One. 2016;11(1):e0147145.
   PubMed Web of Science ®Google Scholar
• Soliman PT, Westin SN, Iglesias DA, et al. Everolimus, letrozole, and metformin in women with advanced or recurrent endometrioid endometrial cancer: a Multi-Center, single arm, phase II study. Clin Cancer Res. 2020;26(3):581–587.
   PubMed Web of Science ®Google Scholar
• Hall C, Stone RL, Gehlot A, et al. Use of metformin in obese women with type I endometrial cancer is associated with a reduced incidence of cancer recurrence. Int J Gynecol Cancer. 2016;26:313–317.
   PubMed Web of Science ®Google Scholar
• Shah MM, Erickson BK, Matin T, et al. Diabetes mellitus and ovarian cancer: more complex than just increasing risk. Gynecol Oncol. 2014;135(2):273–277.
   PubMed Web of Science ®Google Scholar
• Lemańska A, Zaborowski M, Spaczyński M, et al. Do endometrial cancer patients benefit from metformin intake? Ginekol Pol. 2015;86(6):419–423.
   PubMed Web of Science ®Google Scholar
• Al Hilli MM, Bakkum-Gamez JN, Mariani A, et al. The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts. Gynecol Oncol. 2016;140(2):270–276.
   PubMed Web of Science ®Google Scholar
• Arima R, Hautakoski A, Marttila M, et al. Cause-specific mortality in endometrioid endometrial cancer patients with type 2 diabetes using metformin or other types of antidiabetic medication. Gynecol Oncol. 2017;147(3):678–683.
   PubMed Web of Science ®Google Scholar
• Insin P, Prueksaritanond N. Therapeutic use of metformin in diabetes and survival outcomes in endometrial cancer patients with diabetes. Asian Pac J Cancer Prev. 2018;19:1295–1302.
   PubMedGoogle Scholar
• Nevadunsky NS, Van Arsdale A, Strickler HD, et al. Metformin use and endometrial cancer survival. Gynecol Oncol. 2014;132(1):236–240.
   PubMed Web of Science ®Google Scholar
• Seebacher V, Bergmeister B, Grimm C, et al. The prognostic role of metformin in patients with endometrial cancer: a retrospective study. Eur J Obstet Gynecol Reprod Biol. 2016;203:291–296.
   PubMed Web of Science ®Google Scholar
• Zhang ZJ, Li S. The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and Meta-analysis. Diabetes Obes Metab. 2014;16(8):707–710.
   PubMed Web of Science ®Google Scholar
• Stanosz S. An attempt at conservative treatment in selected cases of type I endometrial carcinoma (stage I a/G1) in young women. Eur J Gynaecol Oncol. 2009;30:365–369.
   PubMed Web of Science ®Google Scholar
• Mitsuhashi A, Sato Y, Kiyokawa T, 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):262–266.
   PubMed Web of Science ®Google Scholar
• Mitsuhashi A, Habu Y, Kobayashi T, et al. Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients. J Gynecol Oncol. 2019;30(6):e90.
   PubMed Web of Science ®Google Scholar
• Mitsuhashi A, Kawasaki Y, Hori M, et al. Medroxyprogesterone acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and endometrial carcinoma: trial protocol for a prospective, randomised, open, blinded-endpoint design, dose-response trial (FELICIA trial). BMJ Open. 2020;10(2):e035416.
   PubMed Web of Science ®Google Scholar
• Acosta-Torres S, Murdock T, Matsuno R, et al. The addition of metformin to progestin therapy in the fertility-sparing treatment of women with atypical hyperplasia/endometrial intraepithelial neoplasia or endometrial cancer: little impact on response and low live-birth rates. Gynecol Oncol. 2020;157(2):348–356.
   PubMed Web of Science ®Google Scholar
• Yang BY, Gulinazi Y, Du Y, et al. Metformin plus megestrol acetate compared with MA alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial. BJOG: Int J Obstet Gy. 2020;127(7):848–857.
   PubMed Web of Science ®Google Scholar
• Markowska A, Pawałowska M, Filas V, et al. Does metformin affect ER, PR, IGF-1R, β-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer? Diabetol Metab Syndr. 2013;5(1):76.
   PubMedGoogle Scholar
• Gu CJ, Cheng J, Zhang B, et al. Protopanaxadiol and metformin synergistically inhibit estrogen-mediated proliferation and anti-autophagy effects in endometrial cancer cells. Am J Transl Res. 2017;9(9):4071–4082.
   PubMed Web of Science ®Google Scholar
• Zhang J, Xu H, Zhou X, et al. Role of metformin in inhibiting estrogen-induced proliferation and regulating ERα and ERβ expression in human endometrial cancer cells. Oncol Lett. 2017;14(4):4949–4956.
   PubMed Web of Science ®Google Scholar
• Collins G, Mesiano S, DiFeo A. Effects of metformin on cellular proliferation and steroid hormone receptors in Patient-Derived, Low-Grade endometrial cancer cell lines. Reprod Sci. 2019;26(5):609–618.
   PubMed Web of Science ®Google Scholar
• Pabona JMP, Burnett AF, Brown DM, et al. Metformin promotes anti-tumor biomarkers in human endometrial cancer cells. Reprod Sci. 2020;27(1):267–277.
   PubMed Web of Science ®Google Scholar
• Laskov I, Drudi L, Beauchamp MC, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol. 2014;134(3):607–614.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li MX, Wang H, et al. Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R. Asian Pac J Cancer Prev. 2015;16(1):221–225.
   PubMedGoogle Scholar
• Soliman PT, Zhang Q, Broaddus RR, 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):466–471.
   PubMed Web of Science ®Google Scholar
• Sarfstein R, Friedman Y, Attias-Geva Z, 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.
   PubMed Web of Science ®Google Scholar
• Xie Y, Wang JL, Ji M, et al. Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells. Oncol Lett. 2014;8(5):1993–1999.
   PubMed Web of Science ®Google Scholar
• Cantrell LA, Zhou C, Mendivil A, et al. Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy. Gynecol Oncol. 2010;116(1):92–98.
   PubMed Web of Science ®Google Scholar
• Schuler KM, Rambally BS, DiFurio MJ, et al. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med. 2015;4(2):161–173.
   PubMed Web of Science ®Google Scholar
• Zhuo Z, Wang A, Yu H. Metformin targeting autophagy overcomes progesterone resistance in endometrial carcinoma. Arch Gynecol Obstet. 2016;294(5):1055–1061.
   PubMed Web of Science ®Google Scholar
• Zou J, Hong L, Luo C, et al. Metformin inhibits estrogen-dependent endometrial cancer cell growth by activating the AMPK-FOXO1 signal pathway. Cancer Sci. 2016;107(12):1806–1817.
   PubMed Web of Science ®Google Scholar
• Kilgore J, Jackson AL, Clark LH, et al. Buformin exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells. Am J Transl Res. 2016;8(6):2705–2715.
   PubMed Web of Science ®Google Scholar
• Cai D, Sun H, Qi Y, et al. Insulin-Like growth factor 1/mammalian target of rapamycin and AMP-Activated protein kinase signaling involved in the effects of metformin in the human endometrial cancer. Int J Gynecol Cancer. 2016;26(9):1667–1672.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Sun H, Feng M, et al. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling . Gynecol Endocrinol. 2018;34(5):428–432.
   PubMed Web of Science ®Google Scholar
• Sivalingam VN, Kitson S, McVey R, et al. Measuring the biological effect of presurgical metformin treatment in endometrial cancer. Br J Cancer. 2016;114(3):281–289.
   PubMed Web of Science ®Google Scholar
• Mitsuhashi A, Kiyokawa T, Sato Y, et al. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer. 2014;120(19):2986–2995.
   PubMed Web of Science ®Google Scholar
• Iglesias DA, Yates MS, Van Der Hoeven D, 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):2847–2856.
   PubMed Web of Science ®Google Scholar
• Wallbillich JJ, Josyula S, Saini U, et al. High glucose-mediated STAT3 activation in endometrial cancer is inhibited by metformin: therapeutic implications for endometrial cancer. PLoS One. 2017;12(1):e0170318.
   PubMed Web of Science ®Google Scholar
• Zhong T, Men Y, Lu L, et al. Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene. 2017;36(17):2345–2354.
   PubMed Web of Science ®Google Scholar
• Xie Y, Wang YL, Yu L, et al. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol. 2011;126(3–5):113–120.
   PubMed Web of Science ®Google Scholar
• Niu YJ, Shi HR, Xie Y. Effect and regulation of metformin on endometrial carcinoma subline of progestin-resistance. Zhonghua Fu Chan Ke Za Zhi. 2016;51:135–140.
   PubMedGoogle Scholar
• Fan R, Wang Y, Wang Y, et al. Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-survivin pathway. Am J Transl Res. 2017;9(3):1483–1491.
   PubMed Web of Science ®Google Scholar
• Jiang Y, Chen X, Wei Y, et al. Metformin sensitizes endometrial cancer cells to progestin by targeting TET1 to downregulate glyoxalase I expression. Biomed Pharmacother. 2019;113:108712.
   PubMed Web of Science ®Google Scholar
• Kitson SJ, Maskell Z, Sivalingam VN, et al. PRE-surgical Metformin in Uterine Malignancy (PREMIUM): a multi-center, randomized double-blind, placebo-controlled phase III trial. Clin Cancer Res. 2019;25(8):2424–2432.
   PubMed Web of Science ®Google Scholar
• Hanna RK, Zhou C, Malloy KM, 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):458–469.
   PubMed Web of Science ®Google Scholar
• Uehara T, Mitsuhashi A, Tsuruoka N, et al. Metformin potentiates the anticancer effects of cisplatin under normoxic conditions in vitro. Oncol Rep. 2015;33(2):744–750.
   PubMed Web of Science ®Google Scholar
• Schrauwen S, Coenegrachts L, Cattaneo A, et al. The antitumor effect of metformin with and without carboplatin on primary endometrioid endometrial carcinoma in vivo. Gynecol Oncol. 2015;138(2):378–382.
   PubMed Web of Science ®Google Scholar
• Dong L, Zhou Q, Zhang Z, et al. Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J Obstet Gynaecol Res. 2012;38(8):1077–1085.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Dong L, Sui L, et al. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011;21(2):213–221.
   PubMed Web of Science ®Google Scholar
• Bai M, Yang L, Liao H, et al. Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism. Oncogene. 2018;37(42):5666–5681.
   PubMed Web of Science ®Google Scholar
• Takahashi A, Kimura F, Yamanaka A, et al. Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int. 2014;14:53.
   PubMed Web of Science ®Google Scholar
• Liu Z, Qi S, Zhao X, et al. Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells. Oncotarget. 2016;7(16):21315–21331.
   PubMedGoogle Scholar
• Laskov I, Abou-Nader P, Amin O, et al. Metformin increases E-cadherin in tumors of diabetic patients with endometrial cancer and suppresses epithelial-mesenchymal transition in endometrial cancer cell lines. Int J Gynecol Cancer. 2016;26(7):1213–1221.
   PubMed Web of Science ®Google Scholar
• Kitson SJ, Rosser M, Fischer DP, et al. Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors. Cancers (Basel). 2019;11(5):653.
   Web of Science ®Google Scholar
• Cha JH, Yang WH, Xia W, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell. 2018;71(4):606–620.
   PubMed Web of Science ®Google Scholar
• Xue J, Li L, Li N, et al. Metformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1. Eur J Pharmacol. 2019;859:172541.
   PubMed Web of Science ®Google Scholar
• Lu G, Wu Z, Shang J, et al. The effects of metformin on autophagy. Biomed Pharmacother. 2021;137:111286.
   PubMed Web of Science ®Google Scholar
• Bateman NW, Teng PN, Hope E, et al. Jupiter microtubule-associated homolog 1 (JPT1): a predictive and pharmacodynamic biomarker of metformin response in endometrial cancers. Cancer Med. 2020;9(3):1092–1103.
   PubMed Web of Science ®Google Scholar
• Sivalingam VN, Latif A, Kitson S, et al. Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin. Br J Cancer. 2020;122(1):62–71.
   PubMed Web of Science ®Google Scholar
• Thakur S, Daley B, Gaskins K, et al. Metformin targets mitochondrial glycerophosphate dehydrogenase to control rate of oxidative phosphorylation and growth of thyroid cancer in vitro and in vivo. Clin Cancer Res. 2018;24(16):4030–4043.
   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.
   PubMed Web of Science ®Google Scholar
• Wang JC, Li GY, Wang B, et al. Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation. J Exp Clin Cancer Res. 2019;38(1):235.
   PubMedGoogle Scholar
• Kim HJ, Jin BY, Oh MJ, et al. The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period. Physiol Behav. 2016;154:184–190.
   PubMed Web of Science ®Google Scholar
• Sonnenblick A, Agbor-Tarh D, Bradbury I, et al. Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2-Positive primary breast cancer: analysis from the ALTTO phase III randomized trial. J Clin Oncol. 2017;35(13):1421–1429.
   PubMed Web of Science ®Google Scholar
• Berstein LM, Boyarkina MP, Tsyrlina EV, et al. More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin. Med Oncol. 2011;28(4):1260–1263.
   PubMed Web of Science ®Google Scholar
• Oppong BA, Pharmer LA, Oskar S, et al. The effect of metformin on breast cancer outcomes in patients with type 2 diabetes. Cancer Med. 2014;3(4):1025–1034.
   PubMed Web of Science ®Google Scholar
• Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer. 2012;118(5):1202–1211.
   PubMed Web of Science ®Google Scholar
• Baglia ML, Cui Y, Zheng T, et al. Diabetes medication use in association with survival among patients of breast, colorectal, lung, or gastric cancer. Cancer Res Treat. 2019;51(2):538–546.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Gong C, Wang Z, et al. A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. Oncotarget. 2017;8(48):84224–84236.
   PubMedGoogle Scholar
• Nanni O, Amadori D, De Censi A, et al. Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial. Breast Cancer Res Treat. 2019;174(2):433–442.
   PubMed Web of Science ®Google Scholar
• Cai H, Zhang Y, Han T, et al. Cation-selective transporters are critical to the AMPK-mediated antiproliferative effects of metformin in human breast cancer cells. Int J Mol Sci. 2016;17:2000.
   Google Scholar
• Cai H, Everett RS, Thakker DR. Efficacious dose of metformin for breast cancer therapy is determined by cation transporter expression in tumours. Br J Pharmacol. 2019;176(15):2724–2735.
   PubMed Web of Science ®Google Scholar
• Dos Santos Guimarães I, Ladislau-Magescky T, Tessarollo NG, et al. Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines. Pharmacol Rep. 2018;70(3):409–417.
   PubMed Web of Science ®Google Scholar
• Yang C, Zhao N, Li D, et al. Metformin improves the sensitivity of ovarian cancer cells to chemotherapeutic agents. Oncol Lett. 2019;18:2404–2411.
   PubMed Web of Science ®Google Scholar
• Ricci F, Brunelli L, Affatato R, et al. Overcoming platinum-acquired resistance in ovarian cancer patient-derived xenografts. Ther Adv Med Oncol. 2019;11:1758835919839543.
   Web of Science ®Google Scholar
• Erices R, Cubillos S, Aravena R, et al. Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression. Oncotarget. 2017;8(13):20865–20880.
   PubMedGoogle Scholar
• Garrido MP, Vera C, Vega M, et al. Metformin prevents nerve growth factor-dependent proliferative and proangiogenic effects in epithelial ovarian cancer cells and endothelial cells. Ther Adv Med Oncol. 2018;10:175883591877098.
   Web of Science ®Google Scholar
• Zhang R, Zhang P, Wang H, et al. Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+)CD117(+) ovarian cancer stem cells. Stem Cell Res Ther. 2015;6:262.
   PubMed Web of Science ®Google Scholar
• Gwak H, Kim Y, An H, et al. Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer. Mol Carcinog. 2017;56(2):349–358.
   PubMed Web of Science ®Google Scholar
• Rattan R, Graham RP, Maguire JL, et al. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13(5):483–491.
   PubMed Web of Science ®Google Scholar
• Wang SB, Lei KJ, Liu JP, et al. Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: a retrospective study. Medicine (Baltimore). 2017;96(29):e7605.
   PubMed Web of Science ®Google Scholar
• Romero IL, McCormick A, McEwen KA, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61–67.
   PubMed Web of Science ®Google Scholar
• Kumar S, Meuter A, Thapa P, et al. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer. 2013;119(3):555–562.
   PubMed Web of Science ®Google Scholar
• Urpilainen E, Marttila M, Hautakoski A, et al. The role of metformin and statins in the incidence of epithelial ovarian cancer in type 2 diabetes: a cohort and nested case-control study. BJOG. 2018;125(8):1001–1008.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Zhu J, Zhang H, et al. Metformin plus first-line chemotherapy versus chemotherapy alone in the treatment of epithelial ovarian cancer: a prospective open-label pilot trial. Cancer Chemother Pharmacol. 2019;84(6):1349–1357.
   PubMed Web of Science ®Google Scholar
• Xiao X, He Q, Lu C, et al. Metformin impairs the growth of liver kinase B1-intact cervical cancer cells. Gynecol Oncol. 2012;127(1):249–255.
   PubMed Web of Science ®Google Scholar
• Do MT, Kim HG, Khanal T, et al. Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicol Appl Pharmacol. 2013;271(2):229–238.
   PubMed Web of Science ®Google Scholar
• Cheng K, Hao M. Metformin inhibits TGF-β1-Induced epithelial-to-mesenchymal transition via PKM2 relative-mTOR/p70s6k signaling pathway in cervical carcinoma cells. IJMS. 2016;17(12):2000.
   Google Scholar
• Yudhani RD, Astuti I, Mustofa M, et al. Metformin modulates cyclin D1 and P53 expression to inhibit cell proliferation and to induce apoptosis in cervical cancer cell lines. Asian Pac J Cancer Prev. 2019;20(6):1667–1673.
   PubMedGoogle Scholar
• Hanprasertpong J, Jiamset I, Geater A, et al. The effect of metformin on oncological outcomes in patients with cervical cancer with type 2 diabetes mellitus. Int J Gynecol Cancer. 2017;27(1):131–137.
   PubMed Web of Science ®Google Scholar
• Takiuchi T, Machida H, Hom MS, et al. Association of metformin use and survival outcome in women with cervical cancer. Int J Gynecol Cancer. 2017;27(7):1455–1463.
   PubMed Web of Science ®Google Scholar
• Han K, Pintilie M, Lipscombe LL, et al. Association between metformin use and mortality after cervical cancer in older women with diabetes. Cancer Epidemiol Biomarkers Prev. 2016;25(3):507–512.
   PubMed Web of Science ®Google Scholar
• Meireles CG, Pereira SA, Valadares LP, et al. Effects of metformin on endometrial cancer: Systematic review and Meta-analysis. Gynecol Oncol. 2017;147(1):167–180.
   PubMed Web of Science ®Google Scholar