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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Machida, Tokyo, Japan (M.K., I.S., M.H., M.F., Y.W.); Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan (M.S., F.N., Y.A.); and Antibiotics Laboratory, RIKEN, Wako-shi, Saitama, Japan (S.S., H.O.)

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 procaspase-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.

Address correspondence to: Dr. Masuo Kondoh, Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan. E-mail: masuo{at}ac.shoyaku.ac.jp

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