PT - JOURNAL ARTICLE AU - Andrew J. Burgess AU - Sandra Pavey AU - Robyn Warrener AU - Lisa-Jane K. Hunter AU - Terrence J. Piva AU - Elizabeth A. Musgrove AU - Nicholas Saunders AU - Peter G. Parsons AU - Brian G. Gabrielli TI - Up-Regulation of p21<sup>WAF1/CIP1</sup> by Histone Deacetylase Inhibitors Reduces Their Cytotoxicity DP - 2001 Oct 01 TA - Molecular Pharmacology PG - 828--837 VI - 60 IP - 4 4099 - http://molpharm.aspetjournals.org/content/60/4/828.short 4100 - http://molpharm.aspetjournals.org/content/60/4/828.full SO - Mol Pharmacol2001 Oct 01; 60 AB - Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21+/+ and p21−/− cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors. The American Society for Pharmacology and Experimental Therapeutics