YM155, Inhibitor of survivin, suppresses the growth of human leukemia cells

Kyoung Seob Song. Kosin University College of Medicine, Physiology and 602-703, Republic of Korea

Inhibitor of Apoptosis Protein (IAP) acts the important roles in drug resistance and cancer cell survival in many types of cancer. We investigated the apoptotic effect of IAP inhibitor as well as the suppression of IAP expression in 60 human tumor cell lines for the National Institute’s anti-cancer drug screening program. YM155 is a survivin inhibitor, which is currently being investigated clinical trial. YM155 has an apoptotic effect on several cancer cell lines, like melanoma, pancreatic cancer, or gastric cancer. For transfection, cells were plated in 6-well plates 1 day before transfection with plasmid DNA (1 mg/well) or siRNA (100 pmole/well) using FuGENE6 (Roche; Indianapolis, IN) according to the manufacturer’s instructions. Approximately 24 hours after transfection, cells were maintained in 0.2% serum RPMI media for 16 to 18 hours before treatment with ATP or LPS, and then harvested 24 hours after treatment. The data represent the means 6 SD for at least three independent experiments. Where appropriate, the statistical differences were assessed by Wilcoxon Mann-Whitney test. A P value less than 0.05 was considered statistically significant. Here, we have concentrated leukemia for discovering YM155 roles and its intracellular mechanism. It suppressed the expression of survivin and induced apoptosis (85 - 95%) in time-/dose-dependent manner in HL-60 human leukemia cells at 10 nM. In addition, YM155 could not alter the expression of levels of other IAP protein, like XIAP or cIAP2 protein. Whereas YM155-induced cell death was decreased in cells transfected with wild-type survivin construct compared to cells treated with YM155 alone, cell death was significantly increased by siRNA survivin construct. Furthermore, YM155 could affect the cell cycle in HL-60 cells and YM155-induced cell death was caspase 3-dependent manner. All results are more than three-times independent experiments. These findings indicate that the growth inhibition and suppression of survivin in human leukemia cells by a single compound are enhanced our understanding of developing novel therapeutic drug and have the important implications for cancers in which survivin overexpression occurs.