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

被引:38
作者
Kondoh, M [1 ]
Suzuki, I
Sato, M
Nagashima, F
Simizu, S
Harada, M
Fujii, M
Osada, H
Asakawa, Y
Watanabe, Y
机构
[1] Showa Pharmaceut Univ, Dept Pharmaceut & Biopharmaceut, Tokyo 1948543, Japan
[2] Tokushima Bunri Univ, Fac Pharmaceut Sci, Tokushima 770, Japan
[3] RIKEN, Antibiot Lab, Wako, Saitama 35101, Japan
关键词
D O I
10.1124/jpet.104.069690
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 alpha-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.
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收藏
页码:115 / 122
页数:8
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