BH3 mimetics sensitize bladder cancer cells to cisplatin treatment

Muscle-invasive bladder cancer is most often treated with radical surgery and perioperative cisplatin-based chemotherapy, this represents a challenge for patient survival due to cisplatin resistance and side effects. The antiapoptotic proteins of the Bcl-2-Family are involved in the progression and therapy resistance of cancer, and the development of antagonistic BH3 mimetics is becoming an emerging strategy to combat resistance to chemotherapy. We investigated the effect of BH3 mimetics ABT-737 and obatoclax in HT1197 and HT1376 bladder cancer cells and patient-derived bladder cancer spheroids and their role in cisplatin sensitization by analyzing cell viability, apoptosis and autophagy. Mcl-1 and beclin-1 interaction was assessed by immunoprecipitation and immunofluorescence in HT1197 and HT1376 cell lines and Bcl-xL and Mcl-1 protein expression was evaluated by immunohistochemistry in bladder cancer tissues. Our results revealed a dramatic decrease in cell viability and increased apoptosis in cells treated with the combination of ABT-737 and obatoclax. We also showed that ABT-737 and obatoclax sensitized HT1197 and HT1376 bladder cancer cells, respectively, to cisplatin treatment. We confirmed these findings in tumorspheres derived from HT1197 and HT1376 cells and patient-derived bladder cancer spheroids. Furthermore, combined treatment with cisplatin and obatoclax potentiates the blockade of autophagic flux and apoptosis by disrupting the interaction between Mcl-1 and beclin-1 in HT1376 cells. Finally, in our series of muscle-invasive bladder tumors analyzed by immunohistochemistry more than half of the tumors expressed either Bcl-xL or Mcl-1 proteins. Our results showed that the combinations of ABT-737 or obatoclax with cisplatin may represent alternative therapies for muscle-invasive bladder tumors overexpressing Bcl-xL or Mcl-1 proteins.