title: YM155 induces caspase-8 dependent apoptosis through downregulation of survivin and Mcl-1 in human leukemia cells.
abstract: Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is highly expressed in various kinds of tumors. In the present study, we investigated the cytotoxic mechanism of YM155, a unique small-molecule inhibitor of survivin, in human myelogenous leukemia cells. YM155 potently inhibited the cell growth of HL-60 and U937 cells with the half-maximal inhibitory concentration (IC50) value of 0.3 nM and 0.8 nM, respectively. YM155 significantly suppressed the levels of mRNA expression and protein of survivin in HL-60 and U937 cells. In addition, we also found that YM155 down-regulated the level of Mcl-1, another critical anti-apoptotic protein, in both HL-60 and U937 cells. Treatment of HL-60 and U937 cells with YM155 induced apoptosis concomitant with the activation of caspase-8 and caspase-3. Interestingly, we have found that caspase-8 inhibitor Z-IETD-FMK strongly inhibited YM155-induced apoptosis in HL-60 and U937 cells. When cells were pretreated with Z-IETD-FMK, the activation of caspase-3 was completely abolished, suggesting that caspase-8 may be involved in the activation of caspase-3 during YM155-induced apoptosis. We demonstrated for the first time that YM155 induces caspase-8 dependent apoptosis through downregulation of survivin and Mcl-1 in human leukemia cells.
authors.affiliation: Department of Hematology and Oncology, Faculty of Medicine, University of Fukui, 23 Shimoaizuki, Matsuoka, Eiheiji-Chou, Fukui 910-1193, Japan.
authors.forename: Weiying
authors.initials: W
authors.lastname: Feng
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D020298:U937 Cells
chemical_list: C107489:BIRC5 protein, human; D015853:Cysteine Proteinase Inhibitors; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009285:Naphthoquinones; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D053148:Caspase 3; D053181:Caspase 8; C523798:sepantronium