open access

Vol 93, No 5 (2022)
Review paper
Published online: 2021-12-07
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Metformin in selected malignancies in women

Anna Markowska1, Joanna Stanislawiak-Rudowicz2, Tomasz Kasprzak2, Janina Markowska2, Monika Szarszewska2
·
Pubmed: 35072253
·
Ginekol Pol 2022;93(5):416-421.
Affiliations
  1. Department of Perinatology and Gynecology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
  2. Department of Oncology, Gynaecological Oncology, Poznan University of Medical Sciences, Poznan, Poland

open access

Vol 93, No 5 (2022)
REVIEW PAPERS Gynecology
Published online: 2021-12-07

Abstract

The results of preclinical, epidemiological and clinical studies have shown that metformin, the main drug used in the treatment of type 2 diabetes, has antitumor activity.
Metformin reduces the incidence of malignant neoplasms in various locations, including gynaecological tumours. It lowers morbidity, has a positive effect on the course of the disease and reduces mortality. The mechanism of the antitumor action of metformin is pleiotropic and involves several signalling pathways, including AMPK/mTOR (mitogen activated protein kinase/mammalian target rapamycin), STAT3 (signal transducer and activator of transcription) and numerous factors: NF-KB (nuclear factor kappa), HIF-1 alpha (hypoxia inducible factor 1), IGF-1 (insulin-like growth factor-1), which affect cell proliferation and apoptosis. In addition, metformin eliminates CSCs (cancer stem cells) that are associated with cancer progression, metastasis and resistance to treatment.
The effect of metformin in breast and endometrial cancer is favourable in the vast majority of studies. The results of studies on ovarian and cervical cancer promote metformin as a candidate in the combination treatment of these cancers. More results from meta-analyzes and clinical trials are awaited. It is clearly recognized that metformin as an antidiabetic in women with type 2 diabetes has an advantage over other antidiabetics due to its anticancer activity.

Abstract

The results of preclinical, epidemiological and clinical studies have shown that metformin, the main drug used in the treatment of type 2 diabetes, has antitumor activity.
Metformin reduces the incidence of malignant neoplasms in various locations, including gynaecological tumours. It lowers morbidity, has a positive effect on the course of the disease and reduces mortality. The mechanism of the antitumor action of metformin is pleiotropic and involves several signalling pathways, including AMPK/mTOR (mitogen activated protein kinase/mammalian target rapamycin), STAT3 (signal transducer and activator of transcription) and numerous factors: NF-KB (nuclear factor kappa), HIF-1 alpha (hypoxia inducible factor 1), IGF-1 (insulin-like growth factor-1), which affect cell proliferation and apoptosis. In addition, metformin eliminates CSCs (cancer stem cells) that are associated with cancer progression, metastasis and resistance to treatment.
The effect of metformin in breast and endometrial cancer is favourable in the vast majority of studies. The results of studies on ovarian and cervical cancer promote metformin as a candidate in the combination treatment of these cancers. More results from meta-analyzes and clinical trials are awaited. It is clearly recognized that metformin as an antidiabetic in women with type 2 diabetes has an advantage over other antidiabetics due to its anticancer activity.

Get Citation

Keywords

metformin; breast cancer; endometrial cancer; ovarian cancer; cervical cancer

About this article
Title

Metformin in selected malignancies in women

Journal

Ginekologia Polska

Issue

Vol 93, No 5 (2022)

Article type

Review paper

Pages

416-421

Published online

2021-12-07

Page views

5666

Article views/downloads

1380

DOI

10.5603/GP.a2021.0222

Pubmed

35072253

Bibliographic record

Ginekol Pol 2022;93(5):416-421.

Keywords

metformin
breast cancer
endometrial cancer
ovarian cancer
cervical cancer

Authors

Anna Markowska
Joanna Stanislawiak-Rudowicz
Tomasz Kasprzak
Janina Markowska
Monika Szarszewska

References (48)
  1. Fernandez CJ, George AS, Subrahmanyan NA, et al. Epidemiological link between obesity, type 2 diabetes mellitus and cancer. World J Methodol. 2021; 11(3): 23–45.
  2. Lega IC, Lipscombe LL. Review: diabetes, obesity, and cancer-pathophysiology and clinical implications. Endocr Rev. 2020; 41(1): bnz014.
  3. Vallianou NG, Evangelopoulos A, Kazazis C. Metformin and cancer. Rev Diabet Stud. 2013; 10(4): 228–235.
  4. Lv Z, Guo Y. Metformin and its benefits for various diseases. Front Endocrinol (Lausanne). 2020; 11: 191.
  5. Gandini S, Puntoni M, Heckman-Stoddard BM, et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila). 2014; 7(9): 867–885.
  6. Kalender A, Selvaraj A, Kim S, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase — dependent manner. Cell Metab. 2010; 11(5): 390–401.
  7. Saini N, Yang X. Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells. Acta Biochim Biophys Sin (Shanghai). 2018; 50(2): 133–143.
  8. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209–249.
  9. 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.
  10. De A, Kuppusamy G. Metformin in breast cancer: preclinical and clinical evidence. Curr Probl Cancer. 2020; 44(1): 100488.
  11. 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.
  12. Martin-Castillo B, Pernas S, Dorca J, et al. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget. 2018; 9(86): 35687–35704.
  13. 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.
  14. 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.
  15. Liu H, Scholz C, Zang C, et al. Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res. 2012; 32(5): 1627–1637.
  16. Ariaans G, Jalving M, Vries EG, et al. Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells. BMC Cancer. 2017; 17(1): 232.
  17. Yam C, Esteva FJ, Patel MM, et al. Efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal patients with metastatic, hormone receptor-positive, HER2-negative breast cancer: a phase II study. Invest New Drugs. 2019; 37(2): 345–351.
  18. Nanni O, Amadori D, De Censi A, et al. MYME investigators. 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.
  19. Pimentel I, Lohmann AE, Ennis M, et al. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast. 2019; 48: 17–23.
  20. Friberg E, Orsini N, Mantzoros CS, et al. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007; 50(7): 1365–1374.
  21. Shao Y, Cheng S, Hou J, et al. Insulin is an important risk factor of endometrial cancer among premenopausal women: a case-control study in China. Tumour Biol. 2016; 37(4): 4721–4726.
  22. 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.
  23. Zhou J, Dsupin BA, Giudice LC, et al. Insulin-like growth factor system gene expression in human endometrium during the menstrual cycle. J Clin Endocrinol Metab. 1994; 79(6): 1723–1734.
  24. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012; 12(3): 159–169.
  25. Arcidiacono B, Iiritano S, Nocera A, et al. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res. 2012; 2012: 789174.
  26. 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.
  27. 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.
  28. 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.
  29. Yang BY, Gulinazi Y, Du Y, et al. Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial. BJOG. 2020; 127(7): 848–857.
  30. 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.
  31. Petchsila K, Prueksaritanond N, Insin P, et al. Effect of metformin for decreasing proliferative marker in women with endometrial cancer: a randomized double-blind placebo-controlled trial. Asian Pac J Cancer Prev. 2020; 21(3): 733–741.
  32. Chu D, Wu J, Wang K, et al. Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer. 2018; 18(1): 438.
  33. Gadducci A, Biglia N, Tana R, et al. Metformin use and gynecological cancers: a novel treatment option emerging from drug repositioning. Crit Rev Oncol Hematol. 2016; 105: 73–83.
  34. Rogalska A, Wójcik-Krowiranda K, Forma E, et al. Effects of metformin on the survival of the SKOV-3 ovarian cancer cell line and the expression of genes encoding enzymes involved in O-Glcnacylation [article in Polish]. Ginekol Pol. 2014; 85(7): 521–526.
  35. 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.
  36. Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, et al. The effects of metformin on ovarian cancer: a systematic review. Int J Gynecol Cancer. 2013; 23(9): 1544–1551.
  37. Wen KC, Sung PL, Wu ATH, et al. Neoadjuvant metformin added to conventional chemotherapy synergizes anti-proliferative effects in ovarian cancer. J Ovarian Res. 2020; 13(1): 95.
  38. 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.
  39. Kumar S, Meuter A, Thapa P, et al. Metformin intake associates with better survival in ovarian cancer: a case control study. Cancer. 2013; 119(3): 555–562.
  40. 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.
  41. Shank JJ, Yang K, Ghannam J, et al. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol. 2012; 127(2): 390–397.
  42. Brown JR, Chan DK, Shank JJ, et al. Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer. JCI Insight. 2020; 5(11): e133247.
  43. Urpilainen E, Puistola U, Boussios S, et al. Metformin and ovarian cancer: the evidence. Ann Transl Med. 2020; 8(24): 1711.
  44. Tseng CH, Tseng CH, Tseng CH, et al. Metformin may reduce bladder cancer risk in Taiwanese patients with type 2 diabetes. Acta Diabetol. 2014; 51(2): 295–303.
  45. 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.
  46. 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.
  47. Chen YH, Wang PH, Chen PN, et al. Molecular and cellular mechanisms of metformin in cervical cancer. Cancers (Basel). 2021; 13(11): 2545.
  48. Xia C, Liu C, He Z, et al. Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression. J Exp Clin Cancer Res. 2020; 39(1): 127.

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