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

Masuo Kondoh, Ikue Suzuki, Masao Sato, Fumihiro Nagashima, Siro Simizu, Motoki Harada, Makiko Fujii, Hiroyuki Osada, Yoshinori Asakawa, Yoshiteru Watanabe

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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-11α-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.

Original languageEnglish
Pages (from-to)115-122
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume311
Issue number1
DOIs
Publication statusPublished - 2004 Oct 1

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Kondoh, M., Suzuki, I., Sato, M., Nagashima, F., Simizu, S., Harada, M., Fujii, M., Osada, H., Asakawa, Y., & Watanabe, Y. (2004). Kaurene diterpene induces apoptosis in human leukemia cells partly through a caspase-8-dependent pathway. Journal of Pharmacology and Experimental Therapeutics, 311(1), 115-122. https://doi.org/10.1124/jpet.104.069690