Metformin Intervention—A Panacea for Cancer Treatment?

Abstract

The molecular mechanism of action and the individual influence of various metabolic pathways related to metformin intervention are under current investigation. The available data suggest that metformin provides many advantages, exhibiting anti-inflammatory, anti-cancer, hepatoprotective, cardioprotective, otoprotective, radioprotective, and radio-sensitizing properties depending on cellular context. This literature review was undertaken to provide novel evidence concerning metformin intervention, with a particular emphasis on cancer treatment and prevention. Undoubtedly, the pleiotropic actions associated with metformin include inhibiting inflammatory processes, increasing antioxidant capacity, and improving glycemic and lipid metabolism. Consequently, these characteristics make metformin an attractive medicament to translate to human trials, the promising results of which were also summarized in this review.

Metformin: Is it a drug for all reasons and diseases?

“…In 2013 over 100 clinical trials designed to assess the potential benefits of metformin in the treatment of cancer were listed on the NIHH Clinical Trials government web site [245]; as of May 2022 the number now exceeds 380 with breast cancer featuring dominantly but also trials involving the following cancers: endometrial and ovarian, head and neck squamous cell, multiple myeloma, thyroid, and lymphocytic leukemia. Several systematic reviews and meta-analyses have concluded that there was a reduction in risk of mortality and developing cancer in the range of 14 to >30%, with, in some analyses, increases in risk in subjects treated with sulfonylureas, insulin, and alpha glucosidase inhibitors when compared to treatment with metformin [227,235,[246][247][248][249][250][251]. However, as reported by DeCensi et al, (2010) the use of metformin is not always associated with a significant benefit as seen for colon, breast and prostate cancers where there was no evidence for a reduction in risk [247].…”

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

“…It has also been indicated that activation of AMPK by metformin can have a pleiotropic effect (Zang et al 2004 a, b; Vasamsetti et al 2015 ). Additionally, various studies have shown that treatment with metformin is effective in heart diseases, including cardiotoxicity (Kuburas et al 2022 , O’Neill et al 2022 , Park, Park et al 2022 ), heart failure (Benes et al 2022 , Buczyńska et al 2022 , Hendawy et al 2022 ), atrial fibrillation (Bai et al 2019 ; Liu et al 2020 , Zhou et al 2022 ), coronary heart disease (Hua et al 2018 ; Luo et al 2020 ).…”

Mitochondrial E3 ubiquitin ligase 1 (MUL1) as a novel therapeutic target for diseases associated with mitochondrial dysfunction

“…Metformin has been used for the treatment of metabolic diseases and cancer 56 . The main mechanism described for metformin as an antitumor agent is the activation of the AMPK signaling pathway 56 .…”

“…Metformin has been used for the treatment of metabolic diseases and cancer 56 . The main mechanism described for metformin as an antitumor agent is the activation of the AMPK signaling pathway 56 . In addition, previous studies have shown that metformin decreases Akt activation in several cancer cells.…”

“…56 The main mechanism described for metformin as an antitumor agent is the activation of the AMPK signaling pathway. 56 In addition, previous studies have shown that metformin decreases Akt activation in several cancer cells. Since MUL1 is involved in Akt ubiquitination and degradation in cancer cells, this was the starting point to investigate whether MUL1 is involved in the anticancer mechanism of metformin.…”