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

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.