Mevalonate modulation of cell proliferation and apoptosis

The effects of a combination of simvastatin, a cholesterol lowering agent, and carmustine (BCNU) on experimental C₆ glioma were studied in vitro and in vivo. In vitro simvastatin and BCNU alone inhibited cell proliferation in a dose-dependent fashion. A subliminal concentration of simvastatin (0.1 μM) markedly and synergistically increased the BCNU toxicity to C₆ glioma cells. The combination of simvastatin and BCNU resulted predominantly from the profound retardation of cells in the G₂-M compartment of the cell cycle. A sub-diploid peak (sub-G₁), typical of apoptotic cells, was observed in C₆ cells treated for longer time (72 h) with high concentrations of simvastatin (5 μM-up) or BCNU (50 μM-up) as single agents. Interestingly, evidence of apoptotic death was also seen in cells simultaneously exposed to concentrations of the two drugs that, given alone, did not induce signs of DNA damage. In vivo the combination of simvastatin and BCNU caused a synergistic inhibition of the growth of tumors stereotaxically induced in rats, without any significant increase in toxicity. The results provide in vivo support for the combined use of simvastatin and BCNU in brain tumor treatment.