Histone deacetylase inhibitors enhance the antican

Authors: Chithra D Palani James F Beck Jürgen Sonnemann

Publish Date: 2010/08/03

Volume: 30, Issue: 1, Pages: 25-36

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Abstract

Nutlin3 a smallmolecule MDM2 inhibitor restores p53 function and is thus an appealing candidate for the treatment of cancers retaining wildtype p53 However nutlin3 applied as single agent may be insufficient for cancer therapy Therefore we explored whether the anticancer activity of nutlin3 could be enhanced by combination with histone deacetylase inhibitors HDACi ie vorinostat sodium butyrate MS275 and apicidin We found that nutlin3 and HDACi cooperated to induce cell death in the p53 wildtype cell lines A549 and A2780 but not in the p53 null cell line PC3 as assessed by Alamar Blue assay and flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization Combination index analysis showed that the effect was synergistic For comparison we tested nutlin3 in combination with paclitaxel revealing that nutlin3 antagonized the cytotoxic activity of paclitaxel To shed light on the underlying mechanism of the synergistic action of nutlin3 and HDACi we determined the acetylation status of p53 by immunoblotting and the mRNA levels of MDM2 and MDM4 by realtime RTPCR We observed vorinostat to induce p53 hyperacetylation to reduce the constitutive gene expression of MDM2 and MDM4 and to counteract the nutlin3induced upregulation of MDM2 gene expression In conclusion our study shows that HDACi amplify the antitumor activity of nutlin3—possibly by inducing p53 hyperacetylation and/or MDM2 and/or MDM4 downregulation—suggesting that treatment with a combination of nutlin3 and HDACi may be an effective strategy for treating tumors with wildtype p53

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