title: 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-11alpha-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.
authors.affiliation: Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan. masuo@ac.shoyaku.ac.jp
authors.forename: Masuo
authors.initials: M
authors.lastname: Kondoh
authors.forename: Ikue
authors.initials: I
authors.lastname: Suzuki
authors.forename: Masao
authors.initials: M
authors.lastname: Sato
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Nagashima
authors.forename: Siro
authors.initials: S
authors.lastname: Simizu
authors.forename: Motoki
authors.initials: M
authors.lastname: Harada
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asakawa
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000502:physiology*; D004224:Diterpenes / Q000494:pharmacology; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004347:Drug Interactions; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D045786:Diterpenes, Kaurane; D019253:Proto-Oncogene Proteins c-bcl-2; C002627:kaurene; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases