title: Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Shin
authors.initials: S
authors.lastname: Kim
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Jung
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Jeong
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D032086:Evodia / Q000737:chemistry; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D020298:U937 Cells
chemical_list: D051033:Apoptosis Inducing Factor; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D017382:Reactive Oxygen Species; C049639:evodiamine; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases