Silencing of survivin using YM155 induces apoptosis and chemosensitization in neuroblastomas cells.

OBJECTIVES Aggressive cell growth and chemoresistance are notorious obstacles in neuroblastoma therapy. Accumulating evidence suggests that survivin is preferentially expressed in cancer cells and plays a crucial role in cell division and apoptosis dysfunction. Thus, in the present study, we investigated whether silencing of survivin, using a novel small-molecule survivin suppressant, YM155 could suppress the proliferation and induce chemosensitization of neuroblastoma cells. MATERIALS AND METHODS SH-SY5Y human neuroblastomas cells were treated with YM155 (10 to 500 mM) and/or chemotherapeutic agent cisplatin for 72 hours, and cell viability, apoptosis, mRNA and protein expression level were then evaluated. Furthermore, the efficacy of YM155 combined with cisplatin was further examined in established xenograft models. RESULTS YM155 suppressed expression of survivin, inhibited the proliferation and induced apoptosis in SH-SY5Y cells in a concentration-dependent manner. Reduced levels of survivin sensitized SH-SY5Y to the chemotherapeutic agent cisplatin. YM155 showed antiproliferative effects and induced tumor regression and apoptosis in established SH-SY5Y xenograft models. Cisplatin showed antitumor activity against SH-SY5Y cells, it did not induce survivin upregulation. Combination treatment of YM155 and cisplatin induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression without enhanced body weight loss in the SH-SY5Y xenograft models. CONCLUSIONS The concomitant combination of YM155 with cisplatin induced more intense apoptosis compared with each single treatment in vivo and in vitro. YM155 in combination with cisplatin is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models.