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

## TL;DR

Combining the HDAC inhibitor belinostat with Bcl-xL or Mcl-1 inhibitors may improve treatment for ovarian cancer by boosting cell death.

## Contribution

Belinostat's anticancer effect is enhanced by Bcl-xL or Mcl-1 inhibitors in ovarian cancer models.

## Key findings

- Belinostat increases pro-apoptotic proteins Bim, Puma, and Noxa in ovarian cancer cells.
- Inhibiting Bcl-xL or Mcl-1 sensitizes cancer cells to belinostat's cytotoxic effects.
- Combination therapy shows promise in patient-derived tumor organoids.

## 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‐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.

The pan‐HDAC inhibitor belinostat increases the expression of the pro‐apoptotic proteins Bim, Puma, and Noxa and induces apoptosis in ovarian cancer cell lines and patient‐derived tumor organoids when used at high concentrations. Moreover, inhibiting the anti‐apoptotic proteins Bcl‐xL or Mcl‐1 sensitizes these preclinical models to the cytotoxic effect of belinostat. This study therefore positions belinostat‐based strategies as promising therapies for ovarian cancer.