Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis.

摘要: Ovarian cancer is the leading cause of death from gynecological cancer. The anti-apoptotic protein Bcl-xL frequently overexpressed in ovarian carcinoma which correlates with chemotherapy resistance. It has been demonstrated that cooperates another protein, Mcl-1, to protect cells against apoptosis, and their concomitant inhibition induces massive cell death. Here, we examined interest ABT-737, a potent BH3-mimetic molecule targeting Bcl-xL, both alone combination Mcl-1 modulators, lines. As single agent, ABT-737 was ineffective at promoting four lines tested vitro. However, specific by siRNA dramatically increased sensitivity chemoresistant ABT-737. Platinum compounds also sensitize dose-dependently decreasing expression or increasing pro-apoptotic BH3-only proteins Noxa and, lower extent, Bim. Furthermore, accumulation involved apoptosis occurring response platinum compounds, since were protected its silencing. Moreover, highly cytotoxic ex vivo sliced SKOV3 tumor nodes. However observed these slices strong basal apoptotic alone. Therefore, have revealed modulation Mcl-1/Noxa axis results sensitization could constitute promising therapeutic cancers.