Lovastatin-Induced Proliferation Inhibition and Apoptosis in C6 Glial Cells1

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in cholesterol biosynthesis. HMG-CoA reductase converts HMG-CoA to mevalonate, which is then converted into cholesterol or various isoprenoids through multiple enzymatic steps. In this study, we examined the cytotoxic effects of lovastatin, an HMG-CoA reductase inhibitor, in C6 glial cells. Lovastatin at concentrations higher than 10 μM suppressed cell proliferation and induced cell death, which were prevented completely by mevalonate (300 μM). The data from lactate dehydrogenase assay and fluorescence microscopic assay using Hoechst 33342 and propidium iodide showed that mevalonate at a concentration of 100 μM could prevent lovastatin-induced cell death, whereas it could not prevent lovastatin-induced inhibition of cell proliferation. These data suggest that the lovastatin-induced interruption of cell cycle transition was not sufficient to induce cell death in C6 glial cells. In the presence of lovastatin at concentrations higher than 10 μM, DNA laddering, the typical finding of apoptosis, was identified. Lovastatin-induced apoptosis was prevented by mevalonate (100 μM). Both cycloheximide (0.5 μg/ml) and actinomycin D (0.1 μg/ml) prevented lovastatin-induced DNA laddering. In this study, we demonstrated that the cytotoxic effects of lovastatin fall into two categories: suppression of cell growth and induction of apoptosis in C6 glial cells.