EVOLUTION OF METFORMIN IN BREAST CANCER THERAPY IN LAST TWO DECADES: A REVIEW

Authors

  • R. SARATHI Department of Pharmacy Practice, SRM College of Pharmacy, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
  • S. SARUMATHY Department of Pharmacy Practice, SRM College of Pharmacy, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India
  • V.M. DURAI MAVALAVAN Department of Medical Oncology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India

DOI:

https://doi.org/10.15407/exp-oncology.2024.03.185

Keywords:

metformin, breast cancer, diabetes mellitus, insulin

Abstract

Among women, breast cancer is one of the most prevalent cancers. The disease has a complex etiology, with multiple biological pathways contributing to its development. As insulin signaling has mitogenic effects, glucose is a necessary cellular metabolic substrate, and the growth and metastasis of breast cancer are closely related to cellular glucose metabolism. Anti-diabetic medications have drawn increased attention as a potential treatment for breast cancer. Metformin lowers cancer incidence and death rates in patients with type 2 diabetes, according to epidemiologic studies. Preclinical studies conducted in vivo and in vitro offer fascinating new insights into the cellular mechanisms underlying metformin oncostatic action. We present an overview of the mechanisms of anticancer effects of metformin and discuss its potential function as an adjuvant in the treatment of breast cancer.

References

Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mor­ tality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2018;68(6):394­424. https://doi.org/10.3322/ caac.21492

Sana M, Malik H. Current and emerging breast cancer biomarkers. J Cancer Res Ther. 2015;11(3):508. https://doi. org/10.4103/0973­1482.163698

Tao Z, Shi A, Lu C, et al. Breast cancer: epidemiology and etiology. Cell Biochem Biophys. 2015;72(2):333­338. https:// doi.org/10.1007/s12013­014­0459­6

Roshan MH, Shing YK, Pace NP. Metformin as an adjuvant in breast cancer treatment. SAGE Open Med. 2019; 7:205031211986511. https://doi.org/10.1177/2050312119865114

Bashraheel SS, Kheraldine H, Khalaf S, Moustafa AEA. Metformin and HER2­positive breast cancer: Mechanisms and therapeutic implications. Biomed Pharmacother. 2023;162:114676. https://doi.org/10.1016/j.biopha.2023.114676

Farkhondeh T, Amirabadizadeh A, Aramjoo H, et al. Impact of Metformin on cancer biomarkers in non­diabetic cancer patients: a systematic review and meta­analysis of clinical trials. Curr Oncol. 2021;28(2):1412­1423. https:// doi.org/10.3390/curroncol28020134

Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annu Rev Med. 2015;66(1):17­29. https:// doi.org/10.1146/annurev­med­062613­093128

Vissers PAJ, Cardwell CR, Van De Poll­Franse LV, et al. The association between glucose­lowering drug use and mortality among breast cancer patients with type 2 diabetes. Breast Cancer Res Treat. 2015;150(2):427­437. https:// doi.org/10.1007/s10549­015­3331­5

Della Corte CM, Ciaramella V, Mauro CD, et al. Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells. Oncotarget. 2016;7(4):4265­4278. https://doi. org/10.18632/oncotarget.6559

Morgillo F, Fasano M, Della Corte CM, et al. Results of the safety run­in part of the METAL (METformin in Advanced Lung cancer) study: a multicentre, open­label phase I–II study of metformin with erlotinib in second­line therapy of patients with stage IV non­small­cell lung cancer. ESMO Open. 2017;2(2):e000132. https://doi.org/10.1136/es­ moopen­2016­000132

Cantrell LA, Zhou C, Mendivil A, et al. Metformin is a potent inhibitor of endometrial cancer cell prolifera­ tion—implications for a novel treatment strategy. Gynecol Oncol. 2010;116(1):92­98. https://doi.org/10.1016/j.ygy­ no.2009.09.024

Sarfstein R, Friedman Y, Attias­Geva Z, et al. Metformin downregulates the Insulin/IGF­I signaling pathway and in­ hibits different uterine serous carcinoma (USC) cells proliferation and migration in p53­dependent or ­independent manners. PLoS ONE. 2013;8(4):e61537. https://doi.org/10.1371/journal.pone.0061537

Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. https://doi.org/ 10.3389/fonc.2014.00064

Verkooijen HM, Fioretta G, Vlastos G, et al. Important increase of invasive lobular breast cancer incidence in Ge­ neva, Switzerland. Int J Cancer. 2003;104(6):778­781. https://doi.org/10.1002/ijc.11032

Maher M. Current and emerging treatment regimens for HER2­positive breast cancer. P & T. 2014;39(3): 206­212.

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860­867. https://doi.org/ 10.1038/na­ ture01322

Romagnani S. The Th1/Th2 paradigm. Immunol Today. 1997;18(6):263­266. https://doi.org/10.1016/S0167­ 5699(97)80019­9

DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adap­ tive and innate immune cells during breast cancer progression. Breast Cancer Res. 2007;9(4):212. https://doi.org/ 10.1186/bcr1746

Hu HM, Urba WJ, Fox BA. Gene­modified tumor vaccine with therapeutic potential shifts tumor­specific T cell response from a type 2 to a type 1 cytokine profile. J Immunol. 1998;161(6):3033­3041.

Ostrand­Rosenberg S, Grusby MJ, Clements VK. Cutting edge: STAT6­deficient mice have enhanced tumor immu­ nity to primary and metastatic mammary carcinoma. J Immunol. 2000;165(11):6015­6019. https://doi.org/10.4049/ jimmunol.165.11.6015

Pellegrini P, Berghella AM, Beato TD, et al. Disregulation in TH1 and TH2 subsets of CD4 + T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression. Cancer Immunol Im- munother. 1996;42(1):1­8. https://doi.org/ 10.1007/s002620050244

Tsung K, Meko JB, Peplinski GR, et al. IL­12 induces T helper 1­directed antitumor response. J Immunol. 1997;158(7): 3359–3365.

Russo J, Tahin Q, Lareef MH, et al. Neoplastic transformation of human breast epithelial cells by estrogens anв che­ mical carcinogens. Environ Mol Mutagen. 2002;39(2–3):254­263. https://doi.org/10.1002/em.10052

Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic trans­ formation of breast epithelial cells. PNAS. 2003;100(20):11606­11611. https://doi.org/ 10.1073/pnas.1933744100

Ramteke, Deb, Shepal, Bhat. Hyperglycemia associated metabolic and molecular alterations in cancer risk, progres­ sion, treatment, and mortality. Cancers. 2019;11(9):1402. https://doi.org/10.3390/cancers11091402

Collins KK. The Diabetes­Cancer Link. Diabetes Spectr. 2014;27(4):276­280. https://doi.org/10.2337/diaspect.27.4.276

Price AJ, Allen NE, Appleby PN, et al. Insulin­like growth factor­I concentration and risk of prostate cancer: re­ sults from the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prevent. 2012;21(9):1531­1541. https://doi.org/ 10.1158/1055­9965.EPI­12­0481­T

Cannata D, Fierz Y, Vijayakumar A, LeRoith D. Type 2 Diabetes and cancer: what is the connection?: special feature­ type 2 diabetes and cancer. Mt Sinai J M. 2010;77(2):197­213. https://doi.org/ 10.1002/msj.20167

Shlomai G, Neel B, LeRoith D, Gallagher EJ. Type 2 diabetes mellitus and cancer: the role of pharmacotherapy. J Clin Oncol. 2016;34(35):4261­4269. https://doi.org/10.1200/JCO.2016.67.4044

Tsilidis KK, Kasimis JC, Lopez DS, et al. Type 2 diabetes and cancer: umbrella review of meta­analyses of observa­ tional studies. BMJ. 2015;350:g7607­g7607. https://doi.org/10.1136/bmj.g7607

Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer. Diabetes Care. 2010;33(7):1674­1685. https://doi. org/10.2337/dc10­0666

Ballotari P, Vicentini M, Manicardi V, et al. Diabetes and risk of cancer incidence: results from a population­based cohort study in northern Italy. BMC Cancer. 2017;17(1):703. https://doi.org/10.1186/s12885­017­3696­4

Lao C, Gurney J, Stanley J, et al. Association of diabetes and breast cancer characteristics at diagnosis. Cancer Causes Control. 2023;34(2):103­111. https://doi.org/10.1007/s10552­022­01654­y

Thompson HJ, Neuhouser ML, Lampe JW, et al. Effect of low or high glycemic load diets on experimentally induced mammary carcinogenesis in rats. Mol Nutr Food Res. 2016;60(6):1416­1426. https://doi.org/10.1002/mnfr.201500864

Bose S, Zhang C, Le A. Glucose metabolism in cancer: the Warburg effect and beyond. In: Le A (ed.) The Heterogene- ity of Cancer Metabolism. Springer International Publishing; 2021. p. 3­15. https://doi.org/10.1007/978­3­030­65768­ 0_1

Lop E, Guerrero PE, Duran A, et al. Glycoprotein biomarkers for the detection of pancreatic ductal adenocarcinoma.

World J Gastroenterol. 2018;24(24):2537­2554. https://doi.org/10.3748/wjg.v24.i24.2537

Farmer RE, Ford D, Forbes HJ, et al. Metformin and cancer in type 2 diabetes: a systematic review and comprehen­ sive bias evaluation. Int J Epidemiol. 2016;dyw275. https://doi.org/10.1093/ije/dyw275

Viollet B, Guigas B, Leclerc J, et al. AMP‐activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol. 2009;196(1):81­98. https://doi.org/ 10.1111/j.1748­ 1716.2009.01970.x

Viollet B, Guigas B, Garcia N. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122(6):253­270. https://doi.org/ 10.1042/CS20110386

Brunmair B, Staniek K, Gras F, et al. Thiazolidinediones, like Metformin, inhibit respiratory complex I. Diabetes. 2004;53(4):1052­1059. https://doi.org/10.2337/diabetes.53.4.1052

Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high­glucose–induced endothelial cell death through a mi­ tochondrial permeability transition­dependent process. Diabetes. 2005;54(7):2179­2187. https://doi.org/10.2337/ diabetes.54.7.2179

El­Mir MY, Detaille D, R­Villanueva G, et al. Neuroprotective role of antidiabetic drug Metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci. 2008;34(1):77­87. https://doi.org/10.1007/s12031­007­9002­1

El­Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223­228. https://doi.org/10.1074/jbc.275.1.223

Hinke SA, Martens GA, Cai Y, et al. Methyl succinate antagonises biguanide­induced AMPK‐activation and death of pancreatic beta­cells through restoration of mitochondrial electron transfer. Br J Pharmacol. 2007;150(8):1031­ 1043. https://doi.org/10.1038/sj.bjp.0707189

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti­diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3(Pt 3):607­614.

Batandier C, Guigas B, Detaille D, et al. The ROS production induced by a reverse­electron flux at respiratory­chain complex 1 is hampered by Metformin. J Bioenerg Biomembr. 2006;38(1):33­42. https://doi.org/10.1007/s10863­006­ 9003­8

Kane DA, Anderson EJ, Price Iii JW, et al. Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med. 2010;49(6):1082­1087. https://doi. org/10.1016/j.freeradbiomed.2010.06.022

Jalving M, Gietema JA, Lefrandt JD, etal. Metformin: Takingawaythecandyforcancer? Eur JCancer. 2010;46(13):2369­ 2380. https://doi.org/10.1016/j.ejca.2010.06.012

Queiroz EAIF, Puukila S, Eichler R, et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF­7 breast cancer cells. PLoS ONE. 2014;9(5):e98207. https://doi.org/ 10.1371/ journal.pone.0098207

Sharma P, Kumar S. Metformin inhibits human breast cancer cell growth by promoting apoptosis via a ROS­in­ dependent pathway involving mitochondrial dysfunction: pivotal role of superoxide dismutase (SOD). Cell Oncol. 2018;41(6):637­650. https://doi.org/10.1007/s13402­018­0398­0

Thompson H, Zhu Z, Thompson M, et al. Metformin as an energy restriction mimetic agent for breast cancer preven­ tion. J Carcinog. 2011;10(1):17. https://doi.org/10.4103/1477­3163.83043

Checkley LA, Rudolph MC, Wellberg EA, et al. Metformin accumulation correlates with organic cation transporter 2 protein expression and predicts mammary tumor regression in vivo. Cancer Prev Res. 2017;10(3):198­207. https:// doi.org/10.1158/1940­6207.CAPR­16­0211­T

Bojková B, Kajo K, Kubatka P, et al. Metformin and melatonin improve histopathological outcome of NMU­induced mammary tumors in rats. Pathol Res Pract. 2019;215(4):722­729. https://doi.org/10.1016/j.prp.2019.01.007

Wysocki PJ, Wierusz­Wysocka B. Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for Metformin. Expert Rev Mol Diagn. 2010;10(4):509­519. https://doi.org/10.1586/erm.10.22

Lega IC, Fung K, Austin PC, Lipscombe LL. Metformin and breast cancer stage at diagnosis: a population­based study. Cur Oncol. 2017;24(2):85­91. https://doi.org/10.3747/co.24.3380

Hong JL, Jonsson Funk M, Buse JB, et al. Comparative effect of initiating Metformin versus sulfonylureas on breast cancer risk in older women. Epidemiol. 2017;28(3):446­454. https://doi.org/10.1097/EDE.0000000000000635

Downloads

Published

19.12.2024

How to Cite

SARATHI, R., SARUMATHY, S., & DURAI MAVALAVAN, V. (2024). EVOLUTION OF METFORMIN IN BREAST CANCER THERAPY IN LAST TWO DECADES: A REVIEW. Experimental Oncology, 46(3), 185–191. https://doi.org/10.15407/exp-oncology.2024.03.185