The anticancer effect of the HDAC inhibitor belinostat is enhanced by inhibitors of Bcl-xL or Mcl-1 in ovarian cancer.

Identifying innovative therapeutic strategies is crucial to improve clinical management of ovarian cancer. Previously, we showed that ovarian cancer cell apoptosis can be triggered by inhibiting the anti-apoptotic proteins Bcl-xL and Mcl-1 and/or by inducing their pro-apoptotic partners Bim, Puma, and Noxa. The expression of these pro-apoptotic proteins can be hindered by excessive histone deacetylation, resulting from HDAC overexpression. This study aimed to evaluate whether belinostat, an FDA-approved pan-HDAC inhibitor, could increase Bim, Puma, and/or Noxa expression and induce ovarian cancer cell death, either alone or in combination with strategies targeting Bcl-xL or Mcl-1. Belinostat exerted a cytostatic effect and, at higher concentrations, an apoptotic effect in SKOV3 and IGROV1-R10 ovarian cancer cells. It induced a concentration-dependent increase in Bim, Puma, and Noxa protein expression, while partially repressing that of Bcl-xL. Inhibition of Bcl-xL sensitized both cell lines to belinostat, as did inhibition of Mcl-1 in IGROV1-R10 cells. Interestingly, belinostat's anticancer activity was also enhanced by inhibitors of Bcl-xL or Mcl-1 in patient-derived tumor organoids. This study therefore positions belinostat-based strategies as promising therapies for ovarian cancer.