HMG-CoA reductase inhibitors: role in normal and malignant cells

Abstract

The interest in HMG-CoA reductase inhibitors is presently not only due to their role as cholesterol-lowering agents. Instead the fact that mevalonate (the key metabolite whose synthesis is regulated by HMG-CoA reductase) also serves as a precursor for the biosynthesis of non-sterol isoprenoid products essential for initiation of DNA synthesis and cell growth, has attracted increasing attention during the last 10 years. The two major groups of HMG-CoA reductase inhibitors are constituted by oxysterols (e.g. 25-hydroxycholesterol) and competitive inhibitors (e.g. lovastatin). Oxysterols, which are oxidative products of cholesterol, may play a physiological role in regulation of HMG-CoA reductase activity in mammalian cells. In contrast to the competitive inhibitors their inhibitory effect on HMG-CoA reductase is not complete. On the other hand oxysterols exhibit a variety of effects independent of the inhibition of HMG-CoA reductase. They have, for instance, been found to induce programmed cell death in T cell leukemia cells. The mechanisms lying behind the biological effects of oxysterols are still poorly understood. Post-translational modification of p21ras with isoprene residues (so-called prenylation) has been shown to be essential for the action of this oncoprotein. Additionally, prenylation of nuclear lamins may be of great importance for control of chromosome decondensation after mitosis, which may in turn be critical for expression of cell cycle regulating genes. These connections between HMG-CoA reductase and important cellular functions open the possibility of using HMG-CoA reductase inhibitors, or specific inhibitors of protein prenylation, as anticancer drugs. Another important process dependent on mevalonate is N-linked glycosylation. There are indications that N-linked glycosylation of receptor proteins and several other membrane-bound proteins is necessary for their transport to cell surface. Consequently, inhibition of N-linked glycosylation would lead to a reduced number of functional membrane proteins. This connection between HMG-CoA reductase and expression of membrane glycoproteins may offer a novel pharmacological approach to controlling malignant cell growth. In particular, HMG-CoA reductase inhibitors or glycosylation inhibitors would be useful against such malignant tumors whose uncontrolled growth and tumor progression are dependent on the expression of growth factor receptors or cell adhesion molecules at cell surface.