Up-regulation of p21(WAF1)/(CIP1) by histone deacetylase inhibitors reduces their cytotoxicity

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-r egulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) . In this article, we report that p21 expression was up-regulated by relati vely low doses of the histone deacetylase inhibitor azelaic bishydroxamic a cid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hyperse nsitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mecha nism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) an d p21(-/-) cell lines and direct inhibition of caspase activity, we demonst rate that the reduced sensitivity to killing by ABHA is a consequence of in hibition of apoptosis by up-regulated p21 expression. These data indicate t he enormous potential of therapeutic strategies that bypass the cytoprotect ive effect of p21 and act on the same molecular targets as the histone deac etylase inhibitors.