Multidimensional mechanisms of metformin in cancer treatment.

Abstract

Metformin has been in clinical use for more than half a century, yet its molecular mechanism of action is not entirely understood. Metformin has been shown to have antiproliferative and synergistic effects on various types of cancers. The anticancer effects of metformin are potentially applicable to both diabetic and nondiabetic patients. Areas of ongoing investigation focus on metformin's ability to activate adenosine monophosphate kinase (AMPK), in addition to its effect on Myc mRNA, monocarboxylate transporter 1 (MCT1), hypoxia-inducible factor 1 (HIF1), mammalian target of rapamycin (mTOR), and human epidermal growth factor receptor 2 (HER2). Additional anticancer effects are exhibited by acting on liver kinase B1 (LKB1), CREB-regulated transcription coactivator 2 (CRTC2), nitric oxide, and reactive oxygen species. Further investigation will be focused on elucidating metformin's metal-binding properties and how they may be harnessed for their anticancer effect. The acquired knowledge about metformin properties has expanded the number of targets for drug discovery such as microRNA, hexokinase, adenylate cyclase, transcription factors, various cyclins, and copper. In order to design anticancer drugs that mimic metformin's mechanism of action, binding assay studies must be conducted to fully understand and utilize the AMPK-dependent and independent mechanisms. Metformin's complex mechanisms that can potentially make this drug a multifaceted therapy targeting tumorigenesis in addition to information from ongoing clinical trials implicate that metformin can be a potential chemotherapeutic drug or adjuvant that could prove to be vital to future strategies against several types of cancer.