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Bcl-XL and MCL-1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis.

Abstract：

: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-X(L) expression and apoptosis, whereas recurrence was systematically observed when Bcl-X(L) expression was maintained. Bcl-X(L) down-regulation could thus constitute an interesting chemosensitizing strategy. We showed that a Bcl-X(L)targeted 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-X(L)and MCL-1, we investigated the possibility to avoid recurrence in vitro using 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-X(L) 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-X(L) and MCL-1 allowed a complete annihilation of tumour cells population thus avoiding subsequent recurrence in vitro in cell lines highly refractory to any type of conventional chemotherapy. Therefore, Bcl-X(L) and MCL-1 targeted strategies could constitute an efficient therapeutic tool for the treatment of chemoresistant ovarian carcinoma, in association with conventional chemotherapy.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Brotin E,Meryet-Figuière M,Simonin K,Duval RE,Villedieu M,Leroy-Dudal J,Saison-Behmoaras E,Gauduchon P,Denoyelle C,Poulain L

doi

10.1002/ijc.24787

subject

Has Abstract

pub_date

2010-02-15 00:00:00

pages

885-95

issue

eissn

0020-7136

issn

1097-0215

journal_volume

126

pub_type

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Bcl-XL and MCL-1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis.