Received for publication April 8, 2004.
Revised May 7, 2004.
Accepted for publication May 12, 2004.

Kaurene diterpene induces apoptosis in human leukemia cells partly through a caspase-8-dependent pathway

Abstract

Defects in apoptosis signaling pathways contribute to tumorigenesis and drug resistance, and these defects are often a cause of failure of chemotherapy. Thus, a major goal in chemotherapy 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 factor, 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 cleavage of Bid, a substrate of caspase-8, as well as to the proteolytic processing of pro-caspase-8, indicating that KD treatment induces apoptosis through a caspase-8-dependent pathway. Moreover, overexpression of the drug resistance factor Bcl-2, which is frequently overexpressed in many tumors, failed to confer resistance to KD-induced cytotoxicity. Thus, KD may be a promising experimental cytotoxic agent that possibly points to new strategies to overcome a drug resistance.

Key words: HL-60, apoptosis, caspase, caspase-8, diterpenoid, kaurene

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