Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells

Lovastatin, an HMG-CoA reductase inhibitor, was found to suppress growth an d induce apoptosis in culture human promyelocytic leukaemic cell, HL-60. Ho wever, the mechanisms of lovastatin-induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin-induced apoptosis in HL-60 cells in a dose- and time-dependent m anner. The features of this apoptosis were attenuated by the presence of me valonate, a metabolic intermediate of cholesterol synthesis. Treatment of l ovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase-3, but not caspase-1 activity. Lovasta tin also stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (P ARP), and followed by the appearance of caspase activity and DNA fragmentat ion. Pretreatment with caspase-3 inhibitors, Ac-DEVD-CHO and Z-VAD-FMK, inh ibited lovastatin-induced caspase-3 activity and DNA fragmentation. Further more, we demonstrated that DNase II was involved in the DNA fragmentation i nduced by lovastatin. These results suggested that the mechanism of lovasta tin induced HL-60 cells apoptosis through activation of caspase-3 and DNase II activities.