Metformin and blood cancers

Abstract

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

Figure 1

Galega officinalis (goat's rue). http://www.findmeplants.co.uk/photos/galega_officinalis.jpg

Figure 2

The insulin-dependent (indirect effects) and AMPK-dependent molecular mechanisms (direct effects) underlying the anticancer effects of metformin. AMPK activation in the liver results in decreased insulin and IGF-1 levels and consequent attenuated downstream signaling. In cancer cells, AMPK inhibits PI3K/AKT/mTORC1 signaling directly through the phosphorylation of the Raptor subunit and indirectly through the phosphorylation of the TSC1/2 complex and insulin receptor substrate 1 (IRS1) and the activation of regulated in development and DNA damage response 1 (REDD1). In addition, metformin-induced activation of AMPK leads to the phosphorylation of p53, inducing cycle arrest, apoptosis and autophagy. Inhibition of mTORC1 results in a decrease in global protein synthesis and lipogenesis. Metabolic alterations are also achieved by the inhibition of acetyl-CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase.