SAHA and curcumin combinations co-enhance histone acetylation in human cancer cells but operate antagonistically in exerting cytotoxic effects

Abstract

Suberoylanilide hydroxamic acid (1), as well as other histone deacetylase (HDAC) inhibitors, are promising, targeted anticancer agents. Curcumin (2), a possible antitumor agent, exhibits a HDAC inhibiting effect but with a different mechanism, and was proposed to synergize with other drugs, including HDAC inhibitors. The present study was undertaken to evaluate the possible inhibitory effects of 1 and 2 combinations on the growth of nine human cancer cell lines. Drug combinations resulted in an antagonistic cytotoxic effect, as characterized by the Loewe additivity model, observed in all the cell lines. On the other hand, histone hyperacetylation was synergistically or at least additively induced by 1 and 2 combinations, in four cell lines tested. Despite the enhanced histone acetylation, 1 plus 2 produced a significant antagonism in the induced activation of downstream p21^CIP/WAF1 expression. Concomitantly, induced reactive oxygen species (ROS) production was antagonistically diminished in combinations especially at low concentration of 2. We conclude that 1 and 2 exert an antagonistic cytotoxicity on a variety of cancer cell lines, and suggest that mechanisms mediating their antagonism lie at levels of p21^CIP/WAF1 expression and ROS production, rather than at histone acetylation.

Keywords:

• cancer
• histone deacetylase inhibitors
• SAHA
• curcumin
• drug interaction

Acknowledgements

The authors thank Prof. Song Wu and colleagues in our Institute for the synthesis of 1, Dr Jürgen Sühnel of the Fritz Lipman Institute (Jena, Germany) for providing CombiTool software, and Dr Ting-Chao Chou of the Memorial Sloan-Kettering Cancer Center (New York, USA) for providing CompuSyn software. We are grateful to Prof. Paul Tempst of the Memorial Sloan-Kettering Cancer Center (New York, USA) for critical reading and helpful discussions of the manuscript. This paper was supported by the funding of the National Critical Drug Innovation Project (2009ZX09301-003-9-1) from the Chinese Ministry of Health.