Please use this identifier to cite or link to this item:
Type: Journal article
Title: Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase
Author: Butler, L.
Webb, Y.
Agus, D.
Higgins, B.
Tolentino, T.
Kutko, M.
LaQuaglia, M.
Drobnjak, M.
Cordon-Cardo, C.
Scher, H.
Breslow, R.
Richon, V.
Rifkind, R.
Marks, P.
Citation: Clinical Cancer Research, 2001; 7(4):962-970
Publisher: Amer Assoc Cancer Research
Issue Date: 2001
ISSN: 1078-0432
Statement of
Lisa M. Butler, Yael Webb, David B. Agus, Brian Higgins, Thomas R. Tolentino, Martha C. Kutko, Michael P. LaQuaglia, Marija Drobnjak, Carlos Cordon-Cardo, Howard I. Scher, Ronald Breslow, Victoria M. Richon, Richard A. Rifkind and Paul A. Marks
Abstract: <h4>Purpose</h4>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.<h4>Experimental design and results</h4>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 (ID(50) = 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.<h4>Conclusions</h4>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: Cell Line, Transformed
Tumor Cells, Cultured
Mice, Inbred BALB C
Mice, Nude
Prostatic Neoplasms
Disease Models, Animal
Hydroxamic Acids
Histone Deacetylases
Prostate-Specific Antigen
Antineoplastic Agents
Enzyme Inhibitors
Treatment Outcome
Xenograft Model Antitumor Assays
Cell Division
Cell Differentiation
Cyclin-Dependent Kinase Inhibitor p21
Histone Deacetylase Inhibitors
Description: © 2001 American Association for Cancer Research
Published version:
Appears in Collections:Aurora harvest
Medicine publications

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.