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

Authors: Butler, L. M.; Webb, Y.; Agus, D. B.; Higgins, B.; Tolentino, T. R.; Kutko, M. C.; LaQuaglia, M. P.; Drobnjak, M.; Cordon-Cardo, C.; Scher, H. I.; Breslow, R.; Richon, V. M.; Rifkind, R. A.; Marks, P. A.
Article Title: Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase
Abstract: Purpose: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We 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, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID50 = 100 nm) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared 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.
Keywords: immunohistochemistry; controlled study; treatment outcome; unclassified drug; human cell; histone deacetylase inhibitor; cancer growth; nonhuman; antineoplastic agents; animal cell; mouse; animals; mice; cell division; animal experiment; animal model; cell differentiation; antineoplastic activity; tumor xenograft; tumor cells, cultured; xenograft model antitumor assays; mice, inbred balb c; prostate cancer; prostate-specific antigen; prostatic neoplasms; cancer inhibition; nude mouse; mice, nude; enzyme inhibitors; hydroxamic acids; cell line, transformed; cyclin-dependent kinase inhibitor p21; disease models, animal; cyclins; protein p21; histones; histone deacetylases; histone deacetylase; acetylation; growth inhibition; pyroxamide; humans; human; male; priority journal; article; erythroleukemia cell; aminopyridines
Journal Title: Clinical Cancer Research
Volume: 7
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2001-04-01
Start Page: 962
End Page: 970
Language: English
PUBMED: 11309347
PROVIDER: scopus
Notes: Export Date: 21 May 2015 -- Source: Scopus