Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase

Purpose: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agent s are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (s uberoyl-3-aminopyridineamide hydroxamic acid) is a nem member of this class of compounds that is currently under development as an anticancer agent. W e investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells, Experimental Design and Results: Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, pros tate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused litt le evident toxicity significantly suppressed the growth of s.c. CWR22 prost ate cancer xenografts. Despite the potent growth-inhibitory effects of pyro xamide in this tumor model, serum prostate-specific antigen levels in contr ol versus pyroxamide-treated mice were not significantly different. Pyroxam ide is a potent inhibitor of affinity-purified HDAC1 (ID50 = 100 nM) and ca uses the accumulation of acetylated core histones in MEL cells cultured wit h the agent. Human CWR22 prostate tumor xenografts from mice treated with p yroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetyla tion and increased expression of the cell cycle regulator p21/WAF1, compare d with tumors from vehicle-treated control animals. Conclusions: The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.