1. Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263
- Author
-
Tang, Haikuo, Shao, Huanjie, Yu, Chunrong, and Hou, Jinsong
- Subjects
- *
CANCER treatment , *GENETIC regulation , *APOPTOSIS , *SMALL cell lung cancer , *DIMETHYL sulfoxide , *BIOMOLECULES , *CELL lines , *CANCER cells , *ANTINEOPLASTIC agents , *CELL-mediated cytotoxicity - Abstract
Abstract: YM155, a small-molecule survivin suppressant, exhibits anti-tumor activities in vitro, in vivo and in clinical trials. However, the mechanism of YM155 action remains unclear. In this study, YM155 was administered to a panel of cell lines and the effects of YM155 on Bcl-2 family members were analyzed. Our results show that YM155 strikingly downregulates Mcl-1 in a broad spectrum of cancer cell lines and that the Mcl-1 modulation occurs at the transcriptional level, independently of survivin modulation or caspase activity. Furthermore, analysis of the contribution of Mcl-1 or survivin downregulation to YM155-induced cell death in vitro showed that knockdown of Mcl-1 sensitizes cells to YM155-induced cytotoxicity. Finally, our data demonstrate that downregulation of Mcl-1 by YM155 synergistically lowers the threshold of Bcl-2 family member inhibitor ABT-263-induced cell death. Our findings reveal a novel mechanism by which survivin-independent Mcl-1 suppression plays a critical role in YM155-mediated anti-tumor activities. YM155 treatment in combination with ABT-263 thus affords a new strategy for cancer treatment. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF