Abstract
Metformin (MTF) is a natural compound derived from the legume Galega officinalis. It is the first line antidiabetic drug for type 2 diabetes (T2D) treatment. One of its main antidiabetic effects results from the reduction of hepatic glucose release. First scientific evidence for the anticancer effects of MTF was found in animal research, published in 2001, and some years later a retrospective observational study provided evidence that linked MTF to reduced cancer risk in T2D patients. Its pleiotropic anticancer effects were studied in numerous in vitro and in vivo studies at the molecular and cellular level. Although the majority of these studies demonstrated that MTF is associated with certain anticancer properties, clinical studies and trials provided a mixed view on its beneficial anticancer effects. This review emphasizes the pleiotropic effects of MTF and recent progress made in MTF applications in basic, preclinical, and clinical cancer research.
Highlights
Metformin (MTF) is a 1,1-dimethylbiguanide that is derived from the legume Galega officinalis and was first reported as an antidiabetic drug in 1957 [1]
An expression profiling study in estrogen receptor positive MCF-7 breast cancer cells demonstrated that the antiproliferative effect of MTF is mainly a result of translational suppression of mRNAs of cell cycle regulators and tumor promoters, such as cyclin E2 (CCNE2) and ornithine decarboxylase 1 (ODC1), that are regulated via the mTORC1/4EBP protein pathway [71]
In cervical cancer xenografts in nude mice, MTF treatment reduced tumor growth and angiogenesis and this effect was associated with decreased binding of the inhibitor miR-142-3p to the 3 untranslated region (UTR) of the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) which is known as a tumor promoter in a number of cancer types [76]
Summary
Metformin (MTF) is a 1,1-dimethylbiguanide that is derived from the legume Galega officinalis and was first reported as an antidiabetic drug in 1957 [1]. The main effect of MTF in diabetic patients is to lower glucose levels, resulting in secondary reduction of insulin levels. In contrast to other antidiabetic pharmaceuticals, MTF exhibits only rare side effects such as hypoglycemia, hyperinsulinemia, vitamin B12 deficiency, peripheral neuropathy, or very rarely, lactic acidosis and is less associated with diabetic-related risk factors in overweight patients [8,9,10,11]. Epidemiological studies indicated that obesity and T2D, but not T1D, are associated with elevated relative risk for certain cancer types including liver, biliary tract, pancreatic, colorectal, kidney, bladder, breast, and endometrial cancer [3,14]. MTF exerts its primary main effects at the molecular level as an oxidative phosphorylation (OXPHOS) inhibitor by reversibly inhibiting NADH dehydrogenase (mitochondrial complex I) activity of the respiratory chain, resulting in suppression of ATP production [15,16,17].
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