Sodium Butyrate Enhances the Cytotoxic Effect of Etoposide in HDACi-Sensitive and HDACi-Resistant Transformed Cells.

To overcome the problem of antitumor agent toxicity for normal cells, a combined therapy using drugs with synergistic effects seems to be more effective. We investigated the molecular mechanisms of the sensitization of tumor cells resistant and sensitive to histone deacetylase inhibitors (HDACis) upon etoposide treatment together with the HDACi sodium butyrate (NaBut). We showed that NaBut enhances the cytotoxic effect of etoposide in both HDACi-sensitive and HDACi-resistant cells due to the accumulation of the Bax protein and the dissociation of Ku70-Bax inhibitory complexes. In HDACi-resistant cells, NaBut causes the cytoplasmic accumulation of Bax dissociated from mitochondria in complexes with Ku70 proteins. The increased phosphorylation of the pro-apoptotic Bad protein due to the NaBut-induced activation of Erk and Akt kinases is one of the possible reasons for the accumulation of Bax in the cytoplasm. Despite the inactivation of Bax in HDACi-resistant cells, its accumulation in the cytoplasm upon NaBut treatment makes it possible to enhance the apoptotic response against agents activating the intrinsic pathway of apoptosis. Thus, HDACis involved in combined therapy mediate the sensitization of tumor cells to genotoxic drugs, regardless of the cells' resistance to HDACis.