Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models

Abstract

Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta‐analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta‐analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta‐analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population

“…This association has been reported in several studies, showing that metformin reduces the risk of PCa diagnosis, stabilizes PSA progression, and regulates the expression of multiple proteins that inhibit cellular invasion and migration. [35][36][37] The molecular mechanism behind the effect of metformin may involve its direct action on the tumor and its indirect action on systemic insulin levels 38 and downregulation of the (IGF-1)…”

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer

“…mTOR and acetyl-CoA carboxylase (ACC) inhibition blocks protein synthesis and fatty acid synthesis, respectively. Metformin also acts at the level of REDD1 (mTOR and cyclin D1 inhibitor) and inhibits GTPase Rac1, which leads to a reduction in PC metastases; inhibits the epithelial–mesenchymal transformation (EMT) process; decreases the expression c-MYC oncogene, SOX4 transcription factor and FoxM1 transcription factor, the latter two of which are associated with PC cell migration; increases miR30a expression (tumor suppressor); inhibits Pyruvate Kinase M2 (PKM2) phosphorylation and oxidation; and decreases the incidence of prostate intraepithelial lesions [ 21 , 22 ].…”

“…Another mechanism associated with metformin is a reduction in androgen receptor signaling, which may also be related to AMPK activation. The inhibition of IGF-1 by metformin is also essential, since IGF-1 is associated with PC cell growth [ 21 , 22 ].…”

Empagliflozin: a potential anticancer drug

“…Recently, researchers have studied several diabetes drugs and found them to have potential anticancer activity. Metformin is a first-line therapeutic drug used to treat T2D, and its antitumor effects have been demonstrated in several types of cancer [ 39 – 42 ]. Researchers have found that metformin reduces cancer risk in patients with T2D by activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway [ 43 , 44 ].…”