YM155 induces caspase-8 dependent apoptosis through downregulation of survivin and Mcl-1 in human leukemia cells

Biochem Biophys Res Commun. 2013 May 24;435(1):52-7. doi: 10.1016/j.bbrc.2013.04.036. Epub 2013 Apr 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism*
  • Cell Proliferation / drug effects
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Flow Cytometry
  • Gene Expression Regulation, Leukemic / drug effects
  • HL-60 Cells
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Inhibitory Concentration 50
  • Leukemia / genetics
  • Leukemia / metabolism
  • Leukemia / pathology
  • Molecular Structure
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • Oligopeptides / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survivin
  • U937 Cells

Substances

  • BIRC5 protein, human
  • Cysteine Proteinase Inhibitors
  • Imidazoles
  • Inhibitor of Apoptosis Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Naphthoquinones
  • Oligopeptides
  • Proto-Oncogene Proteins c-bcl-2
  • Survivin
  • YM 155
  • benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone
  • Caspase 3
  • Caspase 8