YM155 sensitizes ovarian cancer cells to cisplatin inducing apoptosis and tumor regression

• CDDP chemoresistant ovarian cancer cells were sensitized to CDDP by the Survivin inhibitor YM155.
• The combination of YM155 plus CDDP induced apoptosis, cell cycle arrest and DNA damage.
• This combination also reduced tumor volume in a xenograft model.

ObjectiveThe objective of this study is to chemosensitize ovarian cancer (OVCa) cells to cisplatin (CDDP) using an inhibitor of Survivin, YM155. The efficacy of YM155 in combination with CDDP was determined in vitro, ex vivo and in vivo.MethodsHuman OVCa cell lines A2780p and their cisplatin-resistant derivative A2780cis, were treated with CDDP, YM155, and the combined treatment (YM155 + CDDP), and cell viability, mRNA and protein expression levels, cell-cycle distribution, and DNA damage were then evaluated. Furthermore, the efficacy of YM155 combined with CDDP was further examined in established primary cell cultures and xenograft models.ResultsThe combination of YM155 with CDDP induced G2/M cell cycle arrest and apoptosis, increased DNA damage, and decreased Survivin levels, especially in A2780cis CDDP-resistant cells. Additionally, YM155 in combination with CDDP sensitized primary cell cultures to CDDP. Studies in vivo showed how this combination significantly decreased the tumor size of OVCa xenografts.ConclusionsOur results demonstrate that in OVCa cells the expression of Survivin did not affect their sensitivity to YM155, suggesting that Survivin was not the only target of YM155. The combination of YM155 with CDDP could be a good option for therapy of CDDP-resistant OVCa, independently of p53 status.