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In ovarian carcinomas, recurrence and acquired chemoresistance are the first leading causes of therapeutic failure and are responsible for the poor overall survival rate. Cisplatin exposure of sensitive cells has been previously associated with a down-regulation of Bcl-XL expression and apoptosis, whereas recurrence was systematically observed when Bcl-XL expression was maintained. Bcl-XL down-regulation could thus constitute an interesting chemosensitizing strategy. We showed that a Bcl-XLtargeted RNA interference strategy efficiently sensitized chemoresistant ovarian carcinoma cells to cisplatin, but some of them were still able to re-proliferate. Considering the possible cooperation between Bcl-XLand MCL-1, we investigated the possibility to avoid recurrencein vitrousing a multi-targeted RNAi strategy directed against these two anti-apoptotic proteins. We showed that their concomitant inhibition lead to massive apoptosis in absence of cisplatin, this multi-targeted RNAi approach being much more efficient than conventional chemotherapy. We thus demonstrated that Bcl-XL and MCL-1 cooperate to constitute together a strong molecular “bolt”, which elimination could be sufficient to allow chemoresistant ovarian carcinoma cells apoptosis. Moreover, we demonstrated that in presence of a low concentration of cisplatin, the concomitant down-regulation of Bcl-XL and MCL-1 allowed a complete annihilation of tumour cells population thus avoiding subsequent recurrencein vitroin cell lines highly refractory to any type of conventional chemotherapy. Therefore, Bcl-XL and MCL-1 targeted strategies could constitute an efficient therapeutic tool for the treatment of chemoresistant ovarian carcinoma, in association with conventional chemotherapy.