Inhibition of Cyclin D1 by Novel Biguanide Derivative YB-004 Increases the Sensitivity of Bladder Cancer to Olaparib via Causing G0 / G1 Arrest.

Abstract

Bladder cancer (BC) is the 10^th most common type of tumor worldwide, and recently approved immunotherapies and FGFR inhibitors have been shown to improve the prognosis of only a very limited subset of BC patients. Thus, the quest for more effective drugs remains an urgent priority for improving the quality of life of more BC patients. Previously, we demonstrated that a novel biguanide YB-004 has potent antitumor activity. In this study, we found that the novel biguanide YB-004 interrupts the cell cycle by reducing the expression of cyclin D1, causing G0/G1 phase arrest, and suppresses homologous recombination (HR) by inhibiting Rad51, thereby increasing DNA damage and blocking BC cell proliferation. Interestingly, our results further revealed that cell accumulation in the S and G2/M phases is the main reason why HR-proficient BC cells are not sensitive to olaparib, as these phases are conducive to HR activation and DNA repair. Thus, YB-004 increased the sensitivity of BC cells to olaparib by reversing the cell cycle changes and HR activation caused by olaparib. Taken together, these findings suggest that the combination of YB-004 with olaparib has great potential for the clinical treatment of HR-proficient BC.