Mivebresib synergized with PZ703b, a novel Bcl-xl PROTAC degrader, induces apoptosis in bladder cancer cells via the mitochondrial pathway

• DOI: 10.1016/j.bbrc.2022.07.045
• Publication Date: 2022-07-16T07:01:29Z
• Authors: Yi Xu; Zhangming Lei; Jianyong Zhu; Lijun Wan
• Keywords: 0301 basic medicine; Sulfonamides; Pyridones; bcl-X Protein; Apoptosis; 3. Good health; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Urinary Bladder Neoplasms; Cell Line, Tumor; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Apoptosis Regulatory Proteins

Bladder cancer is a common urinary cancer that still lacks effective treatments. In the present study, we evaluated the effect of BET inhibitor, mivebresib, in combination with PZ703b, a Bcl-xl PROTAC, on apoptosis in bladder cancer cells. The results revealed that mivebresib and PZ703b synergistically decreased the viabilities of bladder cancer cells. Co-treatment of mivebresib and PZ703b induced apoptosis in bladder cancer cells via the mitochondrial pathway in a caspase-dependent manner. Mechanistically, mivebresib and PZ703b treatment inhibited the expression of Mcl-1 and Bcl-xl, accompanied by upregulation of Bim. Hence, co-treatment of mivebresib and PZ703b rebalanced the level of pro- and anti-apoptotic Bcl-2 proteins in cells. Further investigations showed that forced expression of Mcl-1 or Bcl-xl markedly protected bladder cancer cells from apoptosis induced by combination treatment of mivebresib and PZ703b. In addition, knockdown of Bim also inhibited the cell death induced by mivebresib/PZ703b in bladder cancer cells. In summary, our findings reveal that the combination treatment of mivebresib and PZ703b represents a novel promising strategy to treat bladder cancer.