title: The XIAP inhibitor Embelin enhances TRAIL-induced apoptosis in human leukemia cells by DR4 and DR5 upregulation.
abstract: The present study was designed to explore the effects of low-toxicity Embelin on TRAIL-induced apoptosis and its possible mechanism in human leukemia cells. Our study showed that low-toxicity Embelin enhanced TRAIL-induced apoptosis through DR4 and DR5 upregulation and caspase activation in HL-60 cells. Pan-caspase inhibitor Z-VAD-FMK inhibited cell apoptosis induced by TRAIL alone or combined with low-toxicity Embelin, which indicated the cytotoxic effect is mediated by caspase-dependent apoptosis. Although Embelin is an X chromosome-linked inhibitor-of-apoptosis protein (XIAP) inhibitor, an XIAP independent effect on cell death was detected in HL-60 cells exposed to low-toxicity Embelin and TRAIL. Low-toxicity Embelin upregulated DR4 and DR5 expression to enhance TRAIL-induced apoptosis. The sensitizing effects of Embelin on TRAIL-induced apoptosis were markedly attenuated when DR4/DR5 was knocked down. These data suggested that low-toxicity Embelin enhanced TRAIL-induced cell apoptosis through DR4 and DR5 upregulation, indicating that combination of low-toxicity Embelin and TRAIL may become as a potential antileukemia strategy.
authors.affiliation: Department of Hematology, Shengjing Hospital, China Medical University, Shenyang, 110004, Liaoning, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhuogang
authors.initials: Z
authors.lastname: Liu
authors.forename: Huinan
authors.initials: H
authors.lastname: Jiang
authors.forename: Ke
authors.initials: K
authors.lastname: Zhu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Wenhui
authors.initials: W
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage*; D020169:Caspases / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D016227:Benzoquinones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases; C010945:embelin