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Metformin in Oncology – How Far Is Its Repurposing as an Anticancer Drug?


Authors: Lukáš Pácal;  Kateřina Kaňková
Authors‘ workplace: Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
Published in: Klin Onkol 2020; 33(2): 107-113
Category: Review
doi: https://doi.org/10.14735/amko2020107

Overview

Background: Metformin is the most commonly used antidiabetic drug with a plethora of proven metabolic and cardiovascular beneficial effects and exceptional safety profile. On top of the established metabolic effects, retrospective epidemiologic evidence shows that metformin use is associated with decreased cancer risk and/or improved disease prognosis in diabetic cancer patients on metformin compared to those treated with different antidiabetic drugs. This is a sound argument for eventual repurposing metformin as an adjuvant drug in oncology; however, evidence-based data are currently needed to establish this. Metformin is a biguanide that in the context of type 2 diabetes primarily targets the liver. Metformin inhibits oxidative phosphorylation which leads to the suppression of gluconeogenesis and causes decrease of blood glucose concentration. Mechanisms responsible for metformin anti-neoplastic effect have been investigated extensively, and key events seem to centralize around its ability to induce intracellular energetic stress with subsequent changes of metabolism resulting in cytostatic or cytotoxic action. Large clinical experience with metformin in the treatment of diabetes together with its plausible effects on different cancer cell types initiated a number of clinical trials that tested the hypothesis that metformin might have a beneficial effect in the treatment of cancer.

Purpose: The aim of this review is to compile recent advances in our understanding of metformin antineoplastic effects and to give a summary of the results of recent clinical trials of metformin for treatment of different cancer types.

Keywords:

diabetes – clinical trial – metformin – treatment – cancer – AMPK


Sources

1. He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab 2015; 21 (2): 159–162. doi: 10.1016/ j.cmet.2015.01.003.

2. 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: 607–614.

3. Fullerton MD, Galic S, Marcinko K et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013; 19 (12): 1649–1654. doi: 10.1038/nm.3372.

4. Zhou G, Myers R, Li Y et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108 (8): 1167–1174. doi: 10.1172/JCI13505.

5. Zhang CS, Li M, Ma T et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab 2016; 24 (4): 521–522. doi: 10.1016/j.cmet.2016.09.003.

6. Madiraju AK, Erion DM, Rahimi Y et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510 (7506): 542–546. doi: 10.1038/nature13270.

7. Buse JB, DeFronzo RA, Rosenstock J et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 2016; 39 (2): 198–205. doi: 10.2337/dc15-0488.

8. Song R. Mechanism of metformin: a tale of two sites. Diabetes Care 2016; 39: 187–9.

9. Giovannucci E, Harlan DM, Archer MC et al. Diabetes and cancer: a consensus report. Diabetes Care 2010; 33 (7): 1674–1685. doi: 10.2337/dc10-0666.

10. Renehan AG, Yeh HC, Johnson JA et al. Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer. Diabetologia 2012; 55 (6): 1619–1632. doi: 10.1007/s00125-012-2526-0.

11. Barone BB, Yeh HC, Snyder CF et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 2008; 300 (23): 2754–2764. doi: 10.1001/jama.2008.824.

12. Johnson JA, Carstensen B, Witte D et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia 2012; 55 (6): 1607–1618. doi: 10.1007/s00125-012-2525-1.

13. Jalving M, Gietema JA, Lefrandt JD et al. Metformin: taking away the candy for cancer? Eur J Cancer 2010; 46: 2369–2380. doi: 10.1016/j.ejca.2010.06.012.

14. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414 (6865): 813–820. doi: 10.1038/414813a.

15. Du X, Edelstein D, Obici S et al. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 2006; 116 (4): 1071–1080. doi: 10.1172/JCI23354.

16. Johnson JA, Pollak M. Insulin, glucose and the increased risk of cancer in patients with type 2 diabetes. Diabetologia 2010; 53 (10): 2086–2088. doi: 10.1007/s00125-010-1855-0.

17. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8: 915–928. doi: 10.1038/nrc2536.

18. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem 2008; 114 (1): 63–70. doi: 10.1080/13813450801954451.

19. Reuter S, Gupta SC, Chaturvedi MM et al. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 2010; 49 (11): 1603–1616. doi: 10.1016/j.freeradbiomed.2010.09.006.

20. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 2009; 18 (10): 2569–2578. doi: 10.1158/1055-9965.EPI-09-0372.

21. Kankova K, Hrstka R. Cancer as a metabolic disease and diabetes as a cancer risk? Klin Onkol 2012; 25 (Suppl 2): 2S26–2S31. doi: 10.14735/amko20122S26.

22. Blagih J, Coulombe F, Vincent EE et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015; 42 (1): 41–54. doi: 10.1016/j.immuni.2014.12.030.

23. Pearce EL, Walsh MC, Cejas PJ et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460 (7251): 103–107. doi: 10.1038/nature08097.

24. Eikawa S, Nishida M, Mizukami S et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci USA 2015; 112 (6): 1809–1814. doi: 10.1073/pnas.1417636112.

25. Evans JM, Donnelly LA, Emslie-Smith AM et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330 (7503): 1304–1305. doi: 10.1136/bmj.38415.708634.F7.

26. Noto H, Goto A, Tsujimoto T et al. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 2012; 7 (3): e33411. doi: 10.1371/journal.pone.0033411.

27. Foretz M, Guigas B, Bertrand L et al. Metformin: from mechanisms of action to therapies. Cell Metab 2014; 20 (6): 953–966. doi: 10.1016/j.cmet.2014.09.018.

28. Pollak M. Potential applications for biguanides in oncology. J Clin Invest 2013; 123 (9): 3693–3700. doi: 10.1172/JCI67232.

29. Zhou K, Bellenguez C, Spencer CC et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 2011; 43 (2): 117–120. doi: 10.1038/ng.735.

30. Tomimoto A, Endo H, Sugiyama M et al. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 2008; 99 (11): 2136–2141. doi: 10.1111/j.1349-7006.2008.00933.x.

31. Hosono K, Endo H, Takahashi H et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog 2010; 49 (7): 662–671. doi: 10.1002/mc.20 637.

32. Hosono K, Endo H, Takahashi H et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila) 2010; 3 (9): 1077–1083. doi: 10.1158/1940-6207.CAPR-10-0186.

33. Higurashi T, Takahashi H, Endo H et al. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. BMC Cancer 2012; 12: 118. doi: 10.1186/1471-2407-12-118.

34. Higurashi T, Hosono K, Takahashi H et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol 2016; 17 (4): 475–483. doi: 10.1016/S1470-2045 (15) 00565-3.

35. Miranda VC, Braghiroli MI, Faria LD 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. doi: 10.1016/j.clcc.2016.04.011.

36. El-Fatatry BM, Ibrahim OM, Hussien FZ et al. Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study. Int J Colorectal Dis 2018 32 (12): 1675–1683. doi: 10.1007/s00384-018-3104-9.

37. ClinicalTrials.gov. U.S National Library of Medicine. [online]. Available from: https: //clinicaltrials.gov/.

38. Kordes S, Pollak MN, Zwinderman AH et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2015; 16 (7): 839–847. doi: 10.1016/S1470-2045 (15) 00027-3.

39. Gyawali B, Pantziarka P, Crispino S et al. Does the oncology community have a rejection bias when it comes to repurposed drugs? Ecancermedicalscience 2018; 12: ed76. doi: 10.3332/ecancer.2018.ed76.

40. Reni M, Dugnani E, Cereda S et al. (Ir) relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial. Clin Cancer Res 2016; 22 (5): 1076–1085. doi: 10.1158/1078-0432.CCR-15-1722.

41. 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. doi: 10.18632/oncotarget.20478.

42. Goodwin PJ, Pritchard KI, Ennis M et al. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer 2008; 8 (6): 501–505. doi: 10.3816/CBC.2008.n.060.

43. Campagnoli C, Pasanisi P, Abbà C et al. Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study. Clin Breast Cancer 2012; 12 (3): 175–182. doi: 10.1016/j.clbc.2012.03.004.

44. Hadad SM, Coates P, Jordan LB et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat 2015; 150 (1): 149–155. doi: 10.1007/s10549-015-3307-5.

45. Hadad S, Iwamoto T, Jordan L 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): 783–794. doi: 10.1007/s10549-011-1612-1.

46. DeCensi A, Puntoni M, Gandini S et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat 2014; 148 (1): 81–90. doi: 10.1007/s10549-014-3141-1.

47. Kalinsky K, Crew KD, Refice S et al. Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer. Cancer Invest 2014; 32 (4): 150–157. doi: 10.3109/07357907.2014.889706.

48. Niraula S, Dowling RJ, Ennis M et al. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat 2012; 135 (3): 821–830. doi: 10.1007/s10549-012-2223-1.

49. 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. doi: 10.1200/JCO.2016.69.7722.

50. Davis SR, Robinson PJ, Jane F et al. The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial. Clin Endocrinol (Oxf) 2018; 89 (5): 605–612. doi: 10.1111/cen. 13830.

51. Hanawa S, Mitsuhashi A, Shozu M. Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer. PLoS One 2018; 13 (2): e0192759. doi: 10.1371/journal.pone.0192759.

52. 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. doi: 10.1002/cam4.353.

53. Sivalingam VN, Kitson S, McVey R et al. Measuring the biological effect of presurgical metformin treatment in endometrial cancer. Br J Cancer 2016; 114: 281–289. doi: 10.1038/bjc.2015.453.

54. 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. doi: 10.1002/cncr.28853.

55. 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. doi: 10.1093/annonc/mdv539.

56. Marrone KA, Zhou X, Forde PM et al. A randomized phase II study of metformin plus paclitaxel/carboplatin/bevacizumab in patients with chemotherapy-naïve advanced or metastatic nonsquamous non-small cell lung cancer. Oncologist 2018; 23 (7): 859–865. doi: 10.1634/theoncologist.2017-0465.

57. Parikh AB, Kozuch P, Rohs N et al. Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial. Invest New Drugs 2017; 35 (6): 813–819. doi: 10.1007/s10637-017-0511-7.

58. Hamieh L, McKay RR, Lin X et al. Effect of metformin use on survival outcomes in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2017; 15 (2): 221–229. doi: 10.1016/j.clgc.2016.06.017.

59. Graham GG, Punt J, Arora M et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50 (2): 81–98. doi: 10.2165/11534750-000000000-00000.

60. Bodmer M, Meier C, Krähenbühl S et al. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 2010; 33 (6): 1304–1308. doi: 10.2337/dc09-1791.

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