Metformin and ovarian cancer: the evidence

Abstract

In recent decades, great interest in the off-label use of metformin has arisen as a result of its broad effects on different signaling pathways, with only a few side effects, and low cost. Metformin has been shown to have multiple, dose-dependent preclinical anticancer effects, which can be roughly divided into either direct effects via inhibition of mitochondrial respiratory chain complex I, or indirect effects through lowered glucose, insulin and insulin-like growth factor levels. Further details on in vitro and in vivo anticancer effects specifically in ovarian cancer are continuously reported. Preclinically metformin has clear chemosensitizing effects in ovarian cancer and it is an effective negative regulator of angiogenesis. There are also some epidemiological studies on metformin use in ovarian cancer, but the results of these studies are not as promising as those preclinical studies would indicate. Most preclinical studies have involved metformin concentrations that are many times higher than the pharmacological doses used in patients, which might confound the clinical use of metformin as regards the above-mentioned aspects. In this review we evaluate preclinical and clinical evidence concerning metformin in ovarian cancer treatment.

Keywords: Diabetes; epidemiology; incidence; survival.

Figure 1

Metformin affects cancer cells both directly and indirectly. It activates AMP-activated protein kinase (AMPK), which leads, among other things, to inhibition of mammalian target of rapamycin (mTOR). It also sensitizes tissues to insulin, reduces hepatic gluconeogenesis and decreases circulating insulin levels. This leads indirectly to reduced phosphatidylinositol-3-kinase (PI3K) signaling. In addition, metformin deactivates the downstream signaling molecules ERK and STAT3, which have effects on cell growth and apoptosis (8,12,13). IGF-1, insulin-like growth factor 1; ACC, acetyl-CoA carboxylase; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; p53, tumor protein p53; AKT, serine/theonine-specific protein kinase; ERK, extracellular signal-regulated kinase; TSC2, tuberous sclerosis complex 2; STAT3, signal transducer and activator of transcription 3.