Histone deacetylase inhibitor sodium butyrate enhances the cell killing effect of psoralen plus UVA by attenuating nucleotide excision repair

The use of histone deacetylase inhibitors (HDACI), a promising new class of antineoplastic agents, in combination with cytotoxic agents, such as ionizing radiation and anticancer drugs, has been attracting attention. In this study, we found that sodium butyrate (SB), a widely studied HDACI, remarkably enhanced the cell killing effect of psoralen plus UVA (PUVA) in several cancer cell lines, including skin melanoma. Although a single treatment with PUVA or SB did not greatly affect cell survival, combined treatment with SB and PUVA induced marked apoptosis within 24 hours. The SB-induced augmentation of the cell killing effect was more dramatic in combination with PUVA than with anticancer drugs. The number of double-strand breaks that formed during the repair of PUVA-induced interstrand cross-links (ICL) in chromosomal DNA was significantly reduced in SB-pretreated cells, suggesting that the ability to repair ICL was attenuated by SB. In addition, the incorporation of bromodeoxyuridine and the formation of repair foci of proliferating cell nuclear antigen after PUVA treatment, associated with nucleotide excision repair (NER) in the removal of ICL, were not observed in SB-pretreated cells. Furthermore, the repair kinetics of UV- induced cyclobutane pyrimidine dimers (well-known photolesions repaired by NER) were much slower in SB-pretreated cells than in untreated cells. These results indicated that the enhanced cell killing effect of PUVA by SB was attributable to an attenuated ability to repair DNA and, especially, dysfunctional NER. © 2009 American Association for Cancer Research.