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

Abstract

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-x_L 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-x_L 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-x_L. Inhibition of Bcl-x_L 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-x_L or Mcl-1 in patient-derived tumor organoids. This study therefore positions belinostat-based strategies as promising therapies for ovarian cancer.