Cytotoxic effect of different statins and thiazolidinediones on malignant glioma cells

Abstract

Glioblastoma multiforme is still a tumor with very poor prognosis. Statins are actually used for the treatment of dyslipidemias and thiazolidinediones for improving insulin sensitivity in diabetes. Statins are inhibitors of the cholesterol pathway, while thiazolidinediones are peroxisomal proliferator activator receptor γ (PPAR) agonists. For both, a potent pro-apoptotic activity has been suggested. We compared the antiglioma effect of simvastatin, atorvastatin, lovastatin, pravastatin, rosuvastatin, rosiglitazone, pioglitazone and their combinations at several concentrations on human glioblastoma cell lines U87, U 138, LN 405 and rat RG II. The cytotoxic effect was assessed using a cell proliferation assay after 48 and 144 h. Caspase 3 activity and the addition of isoprenoids and PPAR-y inhibitor GW9662 were assessed. Experiments were as well conducted under hypoxia for 24 h. We demonstrated a significant cytotoxic effect with a combination of statins plus pioglitazone. The effect was observed after 48 h and dramatically increased after 144 h. The combination of 2 types of statins (synthetic and natural) allowed a fivefold dose reduction. Statin effect was reversed with isoprenoids and partially with PPAR-γ antagonists, while thiazolidinediones effect was slightly affected by PPAR-γ antagonists. A marked increase in caspase 3 activity was achieved by combining atorvastatin with lovastatin. Cytotoxicity of the combination of statins and thiazolidinediones did not decrease under hypoxia. The assessed combination of statins with thiazolidinediones shows a synergistic cytotoxic effect against glioblastoma cells in vitro, which could represent a feasible therapeutic schema.