Abstract 1777: Platinum sensitize ovarian carcinoma cells to ABT-737 in vitro and ex vivo through inhibition of Mcl-1

Abstract

Abstract In ovarian carcinoma, chemoresistance is the main responsible for the poor 5-year overall survival, remaining under 30%. Protection against apoptotic cell death is particularly involved in this chemoresistance, and among the observed alterations, overexpression of anti-apoptotic Bcl-2 proteins is of first importance. Among them, Bcl-xL et Mcl-1 appeared to cooperate to protect ovarian cancer cells against apoptosis, thus constituting together pertinent targets. In this context, the use of BH3-mimetic molecule ABT-737, that targets Bcl-xL, could constitute an alternative strategy to reverse the platinum chemoresistance in ovarian carcinoma. However, ABT-737 remaining unable to efficiently inhibit Mcl-1 activity, its clinical use in ovarian carcinoma thus requires defining of another tool able to inhibit Mcl-1. In this study, we investigated in vitro and ex vivo the capacity of platinum derivatives (cisplatin and carboplatin) to inhibit Mcl-1 expression or activity and therefore sensitize ovarian carcinoma cells to ABT-737. SKOV3 and IGROV1-R10 platinum-resistant ovarian cancer cell lines were exposed to these drugs, as single agents or associated, using various exposure protocols in vitro or ex vivo (SKOV3 and IGROV1-R10 xenografted tumor nodes developed in nude mice and subsequently used for slicing and ex vivo treatment). We thus studied apoptosis induction as well as Mcl-1 and pro-apoptotic BH3-only proteins expression. In vitro study: whereas neither cisplatin nor ABT-737 alone presented any toxicity, the association of ABT-737 and platinum was highly cytotoxic in both cell lines. We tested several protocols and showed that ABT-737 must be present during the 24h following carboplatin exposure to allow cell death. These observations are in agreement with the needed down-regulation or inactivation of Mcl-1 by platinum prior or concomitant with ABT-737 exposure to induce cell death. As expected, cisplatin as well as carboplatin were able either to inhibit Mcl-1 expression or to induce BH3-only expression (particularly Noxa and Puma). Moreover, we observed a synergetic effect of the association ABT-737/platinum on BH3-only Bim and Noxa expression, these events being correlated to the ability of platinum to sensitize to ABT-737. Ex vivo study: we confirmed these observations in SKOV3 and IGROV1-R10 ex vivo tumor slices models. Whereas ABT-737 and platinum derivatives remained poorly cytotoxic or completely ineffective as single agents, their association was highly cytotoxic. In conclusion, this strategy associating ABT-737 to platinum appears as an attractive way to reverse resistance to platinum derivatives that remain the most active drugs in ovarian cancer. Moreover, this study presents platinum derivatives as pertinent sensitizers to ABT-737, through its direct or indirect Mcl-1 inhibition, opening new perspectives for the clinical use of this promising BH3-mimetic molecule. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1777. doi:10.1158/1538-7445.AM2011-1777