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Research Articles: Targets

Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells

¹ Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu, South Korea and ² Department of Anatomy and Cell Biology, Dong-A University College of Medicine (BK21 Program), and Medical Science Research Center, Busan, South Korea

Requests for reprints: Taeg Kyu Kwon, Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea. Phone: 82-53-250-7846. Fax: 82-53-250-7074. E-mail: kwontk{at}dsmc.or.kr; Young Hyun Yoo, Department of Anatomy and Cell Biology, Dong-A University College of Medicine (BK21 Program) and Medical Science Research Center, Busan 602-714, South Korea. Phone: 82-51-240-2926. E-mail: yhyoo{at}daunet.donga.ac.kr

Evodiamine is one of the major bioactive compounds that have been isolated and purified from the fruit of Evodiae fructus. Evodiamine exhibits antitumor activities against the human tumor cells, including multidrug-resistant tumor cells. However, the molecular mechanism involved in cell death induced by evodiamine treatment remains poorly understood. In the present study, we showed that evodiamine activated the caspase-dependent apoptotic pathway. This apoptosis was only partially inhibited by a pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, which suggested that evodiamine-induced apoptosis in leukemic U937 cells is partially caspase independent. We observed the nuclear translocation of apoptosis-inducing factor in evodiamine-induced apoptosis of U937 cells, which may be responsible for the caspase-independent apoptotic execution. We next showed that evodiamine induced the substantial amount of apoptosis both in Bcl-2- and Akt-overexpressing U937 cells but not in human peripheral blood mononuclear cells. Although benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone inhibited caspase activity in Bcl-2-overexpressing U937 cells, it completely prevented neither the induction of apoptosis or the nuclear translocation of apoptosis-inducing factor, which suggests that evodiamine is, at least in part, able to bypass the resistance of leukemia cells via caspase-independent apoptotic pathways. Thus, therapeutic strategy using evodiamine may warrant further evaluation. [Mol Cancer Ther 2006;5(9):2398–409]

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Received 3/28/06; revised 6/21/06; accepted 7/11/06.