Cytotoxic effects of statins and thiazolidinediones on meningioma cells

Abstract

Statins are inhibitors of the cholesterol synthesis pathway with pleiotropic effects, while thiazolidinediones (TDZ) are peroxisomal proliferator activator receptor γ (PPAR-γ) agonists with potent proapoptotic activity. For both groups of substances a cytotoxic effect against several human tumors is presumed. Direct comparison of several statins and TDZ has not been performed on meningioma cells until now. We compared the antiproliferative/cytotoxic effect of five statins, two TDZ, and their combinations on various human meningioma cell lines and nontumorous cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, cell cycle analysis, and caspase-3 assay. Simvastatin (SMV) and its combination with the TDZ pioglitazone (PGZ) turned out to be the most effective treatment. After 96 h the 50% inhibition concentration (IC(50)) of SMV in MTT assays for two more sensitive meningioma cell lines (one benign and one malignant) was below 0.9 μM, while the IC(50) was 2.8 μM or higher for two other meningioma lines. Fluorescence-activated cell sorting (FACS) analysis suggested that MTT results mostly represented cytotoxic rather than antiproliferative effects. Strong caspase-3 induction suggested participation of intrinsic apoptosis in meningioma cell death. In contrast, SMV showed no substantial effects on fibroblasts and astrocytes. Addition of 40 μM PGZ significantly decreased the fraction of clonogenic cells in soft-agar assays, as compared with 2.8 μM SMV alone. Taken together, SMV showed a significant cytotoxic effect against human meningioma cells, which was moderately enhanced by PGZ.