title: Reactive oxygen species-independent rapid initiation of mitochondrial apoptotic pathway by chelerythrine.
abstract: Chelerythrine, formerly identified as a protein kinase C inhibitor, has also been shown to inhibit the anti-apoptotic Bcl-2 family proteins. However, recent studies have now demonstrated that chelerythrine can induce the loss of mitochondrial membrane potential (ΔΨm), a membrane permeability transition (MPT), and the subsequent activation of the mitochondrial apoptotic pathway, even in the cells deficient in Bax and Bak. This suggests the existence of an alternative Bax/Bak-independent pathway for apoptosis. The generation of reactive oxygen species (ROS) from the mitochondrial electron transport chain (ETC) is also implicated in the cytotoxity elicited by chelerythrine. In our current study, we show that chelerythrine induces the rapid apoptotic death of H9c2 cardiomyocyte-derived cells within 8 min of treatment. The proteolytic activation of caspase9 and caspase3, crucial mediators of the mitochondrial apoptotic pathway, are also observed within 6 min of exposure to this drug. The generation of ROS is detected but at only marginal levels in the treated cells. The inhibition of the mitochondrial ETC by rotenone and malonate had almost no effects on ROS generation but in both cases effectively inhibited both cell death and the caspase activation induced by chelerythrine. Hence, chelerythrine initiates the rapid mitochondrial apoptotic death of H9c2 cardiomyoblastoma cells in a manner that is likely independent of the generation of ROS from mitochondria.
authors.affiliation: Section of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Funakoshi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Aki
authors.forename: Haruka
authors.initials: H
authors.lastname: Nakayama
authors.forename: Yumi
authors.initials: Y
authors.lastname: Watanuki
authors.forename: Satoko
authors.initials: S
authors.lastname: Imori
authors.forename: Koichi
authors.initials: K
authors.lastname: Uemura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006338:Heart Neoplasms / Q000378:metabolism / Q000473:pathology*; D008314:Malonates / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009379:Neoplasms, Muscle Tissue / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D008314:Malonates; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; C030290:malonic acid; C016299:chelerythrine; D020169:Caspases