HDAC Class I Inhibitor Domatinostat Induces Apoptosis Preferentially in Glioma Stem Cells Through p53-Dependent and -Independent Activation of BAX Expression.

Domatinostat is an inhibitor of class I histone deacetylases, whose safety and efficacy as a cancer therapeutic has been demonstrated in a recent phase II study in patients with esophagogastric adenocarcinoma. We previously showed that domatinostat exhibited preferential cytotoxic activity against glioma stem cells (GSCs) compared to their differentiated counterparts. However, the underlying mechanism behind the preferential cytotoxicity is yet to be elucidated. In this study, we examined the effects of domatinostat treatment, as well as those of the knockdown of p53 or BAX or of the overexpression of BAX, on the expression of p53, BAX, and cleaved caspase substrates and on cell death in GSCs and their isogenic, differentiated counterparts. The results obtained indicated that domatinostat induced caspase-dependent apoptotic cell death preferentially in GSCs, which was accompanied by increased BAX expression in GSCs, but not in their differentiated counterparts. The increased BAX expression was required for domatinostat-induced GSC death, whereas BAX overexpression was sufficient to induce cell death in both GSCs and their differentiated counterparts. Notably, the expression of BAX after domatinostat treatment showed an early, p53-independent increase followed by a late, p53-dependent one. Together, the results suggest that the unique ability of domatinostat to activate the p53-dependent and -independent programs of BAX expression selectively in GSCs could account for its preferential cytotoxicity against GSCs. Our findings may also help guide the selection of patients with glioblastoma, and possibly those with other types of cancer, who are most likely to benefit from domatinostat treatment and optimize the treatment strategy for such patients.