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: Weiying Feng, Akira Yoshida, Takanori Ueda
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 435 Issue 1 Pg. 52-7 (May 24 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23618862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 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
• benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone
• Caspase 3
• Caspase 8
• sepantronium

Topics

• 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, pharmacology)
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Inhibitory Concentration 50
• Leukemia (genetics, metabolism, pathology)
• Molecular Structure
• Myeloid Cell Leukemia Sequence 1 Protein
• Naphthoquinones (chemistry, pharmacology)
• Oligopeptides (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Survivin
• U937 Cells