Treatment of malignant pleural mesothelioma (MPM) with cisplatin often leads to acquired resistance with ensuing therapy failure, which may be the consequence of decreased apoptosis due overexpression of anti-apoptotic Bcl-2 family proteins or inhibitor of apoptosis (IAP) family proteins. Pro-apoptotic BH3-mimetics that antagonize the anti-apoptotic Bcl-2 protein family members and IAP inhibitors, which target the IAP family, could re-sensitize resistant MPM cells to cisplatin. We studied the effects of cisplatin, IAP inhibitor AT-406 and the BH3-mimetics ABT-737 and obatoclax on apoptosis and cytotoxicity in a cisplatin-resistant subline of MPM (P31res) and its parental cell line (P31). We used protein arrays and Western blot to study the differences between P31 and P31res cells in apoptosis signal transduction as well as the effects of cisplatin and obatoclax . P31res cells displayed changes in the Bcl-2 family protein expression in response to cisplatin and a massive inhibition of Bcl-x expression by obatoclax. The IAP-binding proteins Smac/Diablo and Htra2 were downregulated in P31res cells and cisplatin further downregulated Htra2. This suggested that Bcl-2 family proteins and IAP-related proteins may play a role in cisplatin resistance in the studied cell lines. Obatoclax decreased IAP protein expression in both P31 and P31res subline cells but addition of cisplatin abolished this effect in P31res cells. The IAP inhibitor AT-406 and BH3-mimetic obatoclax increased cisplatin cytotoxicity and apoptosis. Combined use of obatoclax with IAP inhibition only had a slight additive effect. This warrants further studies of targeting anti-apoptotic Bcl-2 family proteins and IAPs in malignant pleural mesothelioma.
