Kaurene Diterpene Induces Apoptosis in Human Leukemia Cells Partly through a Caspase-8-Dependent Pathway

Defects in apoptosis signaling pathways contribute to tumori-genesis and drug resistance, and these defects are often a cause of failure of chemotherapy. Thus, a major goal in che-motherapy is to find cytotoxic agents that restore the ability of tumor cells to undergo apoptosis. We previously found that an Ent-kaurene diterpene, Ent-11-hydroxy-16-kauren-15-one (KD), induced apoptosis in human promyelocytic leukemia HL-60 cells. Here, we found that caspase-8, an apoptotic fac-tor, is involved in KD-induced apoptosis. Although treatment of HL-60 cells with KD resulted in the activation of caspase-8 and-9, a caspase-8-specific inhibitor but not a caspase-9-specific inhibitor attenuated KD-induced apoptosis. Expression of a catalytically inactive caspase-8 partly attenuated KD-induced apoptosis. Treatment with KD led to a time-dependent cleav-age of Bid, a substrate of caspase-8, as well as to the proteo