The balance between induction and inhibition of mevalonate pathway regulates cancer suppression by statins: A review of molecular mechanisms.

Abstract

Statins are widely used drugs for their role in decreasing cholesterol in hypercholesterolemic patients. Statins through inhibition of Hydroxy Methyl Glutaryl-CoA Reductase (HMGCR), the main enzyme of the cholesterol biosynthesis pathway, inhibit mevalonate pathway that provides isoprenoids for prenylation of different proteins such as Ras superfamily which has an essential role in cancer developing. Inhibition of the mevalonate/isoprenoid pathway is the cause of the cholesterol independent effects of statins or pleotropic effects. Depending on their penetrance into the extra-hepatic cells, statins have different effects on mevalonate/isoprenoid pathway. Lipophilic statins diffuse into all cells and hydrophilic ones use a variety of membrane transporters to gain access to cells other than hepatocytes. It has been suggested that the lower accessibility of statins for extra-hepatic tissues may result in the compensatory induction of mevalonate/isoprenoid pathway and so cancer developing. However, most of the population-based studies have demonstrated that statins have no effect on cancer developing, even decrease the risk of different types of cancer. In this review we focus on the cancer developing "potentials" and the anti-cancer "activities" of statins regarding the effects of statins on mevalonate/isoprenoid pathway in the liver and extra-hepatic tissues.