Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs

Although DNA-damaging agents are among the most effective anticancer drugs in clinical use, their overall effectiveness is limited by the development of cross-resistance to these drugs. Given that histone deacetylase (HDAC) inhibitors increase the acetylation of core histones, resulting in an open chromatin configuration that is more accessible to DNA-targeting agents, we examined whether HDAC inhibitors might enhance the cytotoxicity of DNA-damaging drugs in six human ovarian tumor cell lines that exhibit different cisplatin sensitivities. Low concentrations of HDAC inhibitors, which alone exhibited little cytotoxicity, markedly enhanced the induction of apoptotic cell death not only by cisplatin but also by a wide variety of DNA-targeting anticancer drugs in these tumor cell lines, irrespective of their sensitivities to the respective drugs. In contrast, HDAC inhibitors did not increase the cytotoxicity of metabolic antagonists or microtubule-targeting agents. HDAC inhibitors potentiated both the phosphorylation of histone H2AX on serine-139 (a marker of DNA double-strand breaks) as well as the accumulation of reactive oxygen species induced by DNA-damaging agents in tumor cells. The enhanced generation of reactive oxygen species appeared to be responsible for the enhanced apoptotic cell death induced by the combination of these drugs. These results indicate that the combination of an HDAC inhibitor with a wide variety of DNA-damaging agents is a promising chemotherapeutic strategy for the eradication of tumor cells, regardless of whether the cells are sensitive or resistant to the DNA-damaging anticancer drugs.