Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Abstract

The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

“…Accordingly, simvastatin treatment restored doxorubicin sensitivity to the level of the parental cell line. Mevalonate pathway overactivation is a frequent event in carcinogenesis [20][21][22], and the rate-limiting enzyme of the pathway, 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGCR), has been even classified as a metabolic oncogene [28]. The consequences of mevalonate pathway activation can be relevant not only for cancer development per se, but also for therapy response.…”

“…The consequences of mevalonate pathway activation can be relevant not only for cancer development per se, but also for therapy response. Several mechanisms may contribute, reflecting different outputs of the pathway [20][21][22]. One of these is isoprenylation of Ras, Rac and Rho oncoproteins, which is crucial for their membrane localization and subsequent signal transduction.…”

“…Importantly, pharmacologic inhibition of the pathway completely abolished this novel type of therapy resistance. In view of a recent intensive debate about the pharmacological application of mevalonate synthesis inhibitors-statins-in cancer treatment [20][21][22], this new experimental model could be instrumental in formulating a new therapeutic strategy in some cases of refractory chemoresistant bladder cancer.…”

Addressing corticosteroid insensitivity in adults with asthma

“…Statins reduce cholesterol biosynthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and in addition have pleiotropic immunomodulatory effects that may be of value for the treatment of chronic inflammatory diseases [144,145]. Preclinical in vitro and in vivo studies, including experimental models of allergic [146] and tobacco-smokeinduced lung inflammation [147] found that statins reduce components of airway inflammation potentially relevant to the pathogenesis of asthma and smoke-induced airway diseases.…”

Reduction of cholesterol and markers of oxidation in serum of hypercholestrolemic patients treated with lycosome formulation of simvastatin

“…All statins inhibit within the liver conversion of HMG-CoA to mevalonate, a cholesterol precursor. 6 This process takes place in hepatocytes and the degree of hepatic HMG-CoA reductase inhibition predetermines the extent of the cholesterol-lowering effect of statins. 7 Inhibition of HMG-CoA reductase in extrahepatic cells and tissues is unlikely to affect lipid homeostasis and serum lipid level.…”