Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Abstract

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

“…In the preclinical setting, metformin increased internalization of caveolin-1/T-DM1 and sensitivity to T-DM1 treatment through suppression of the HIF-responsive Akt/MAPK pathway (159). Metformin is one of the main metabolically targeted drugs currently under investigation in breast cancer with (combination) trials ongoing in the setting of prevention and maintenance (160). However, so far no benefit of metformin has been demonstrated in randomized trials, which may be related to compensatory increases in glucose uptake and transcription of many genes involved in mitochondrial metabolism that occur already within 1-2 weeks of treatment (161).…”

Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

“…Sawayama H. et al [ 78 ] studied the influence of GLUT-1 inhibition on cisplatin response in esophageal cancer and found that the inhibition of GLUT-1 using miRNAs or specific inhibitors improved the sensitivity to low dose cisplatin treatment [ 44 , 78 ]. Metformin, a widely used antidiabetic drug, is also being investigated for its anticancer potential [ 45 ]. Metformin can inhibit proliferation and induce apoptosis in BC cells by downregulating all isoforms of GLUT ( Figure 1 A) [ 46 ].…”

“…The use of anti-glycolytic inhibitors is beneficial in cancers in hypoxic conditions or with mitochondrial defects. Metformin, an antidiabetic drug, clinically showed improved chemotherapeutic and radiotherapeutic activity in combination with anticancer agents [ 45 ]. The combination of a more potent version of metformin, called phenformin (50 times), and oxamate was reported to be effective in various cancer cells, including BC [ 225 ].…”

Glucose 6-phosphate dehydrogenase inhibition sensitizes melanoma cells to metformin treatment

“…However, metformin seems to have low efficacy as monotherapy against a number of different tumors, including melanoma [ 20 ]. Thus, the potential adjuvant role of metformin is currently being investigated in several clinical trials [ 5 , 16 , [21] , [22] , [23] , [24] ] and, high efforts are being made to improve metformin performance.…”