This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Butler, L. M. Articles by Marks, P. A. Search for Related Content PubMed PubMed Citation Articles by Butler, L. M. Articles by Marks, P. A.

Inhibition of Transformed Cell Growth and Induction of Cellular Differentiation by Pyroxamide, an Inhibitor of Histone Deacetylase¹

Cell Biology Program [L. M. B., Y. W., T. R. T., M. C. K., V. M. R., R. A. R., P. A. M.], Laboratory of Tumor Biology [D. B. A., B. H.], Department of Surgery [M. P. L.], Department of Pathology [M. D., C. C-C.], Genitourinary Oncology Service [H. I. S.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Department of Chemistry, Columbia University, New York, New York 10027 [Y. W., R. B.]; and Department of Pediatrics, Joan and Sandford I. Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021 [M. C. K.]

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.

This article has been cited by other articles:

				A. Hadnagy, R. Beaulieu, and D. Balicki Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics Mol. Cancer Ther., April 1, 2008; 7(4): 740 - 748. [Abstract] [Full Text] [PDF]

				D. L. Marrocco, W. D. Tilley, T. Bianco-Miotto, A. Evdokiou, H. I. Scher, R. A. Rifkind, P. A. Marks, V. M. Richon, and L. M. Butler Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation Mol. Cancer Ther., January 1, 2007; 6(1): 51 - 60. [Abstract] [Full Text] [PDF]

				H. Matsushita, P. P. Scaglioni, M. Bhaumik, E. M. Rego, L. F. Cai, S. M. Majid, H. Miyachi, A. Kakizuka, W. H. Miller Jr., and P. P. Pandolfi In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR{alpha} blockade in the pathogenesis of acute promyelocytic leukemia J. Exp. Med., April 17, 2006; 203(4): 821 - 828. [Abstract] [Full Text] [PDF]

				M. R. Acharya, A. Sparreboom, J. Venitz, and W. D. Figg Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review Mol. Pharmacol., October 1, 2005; 68(4): 917 - 932. [Abstract] [Full Text] [PDF]

				P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF]

				L.-C. Li, P. R. Carroll, and R. Dahiya Epigenetic Changes in Prostate Cancer: Implication for Diagnosis and Treatment J Natl Cancer Inst, January 19, 2005; 97(2): 103 - 115. [Abstract] [Full Text] [PDF]

				L. C. Hsi, X. Xi, R. Lotan, I. Shureiqi, and S. M. Lippman The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Apoptosis via Induction of 15-Lipoxygenase-1 in Colorectal Cancer Cells Cancer Res., December 1, 2004; 64(23): 8778 - 8781. [Abstract] [Full Text] [PDF]

				J.-H. Park, Y. Jung, T. Y. Kim, S. G. Kim, H.-S. Jong, J. W. Lee, D.-K. Kim, J.-S. Lee, N. K. Kim, T.-Y. Kim, et al. Class I Histone Deacetylase-Selective Novel Synthetic Inhibitors Potently Inhibit Human Tumor Proliferation Clin. Cancer Res., August 1, 2004; 10(15): 5271 - 5281. [Abstract] [Full Text] [PDF]

				M. D. Hofer, R. Kuefer, S. Varambally, H. Li, J. Ma, G. I. Shapiro, J. E. Gschwend, R. E. Hautmann, M. G. Sanda, K. Giehl, et al. The Role of Metastasis-Associated Protein 1 in Prostate Cancer Progression Cancer Res., February 1, 2004; 64(3): 825 - 829. [Abstract] [Full Text] [PDF]

				M. C. Kutko, R. D. Glick, L. M. Butler, D. C. Coffey, R. A. Rifkind, P. A. Marks, V. M. Richon, and M. P. LaQuaglia Histone Deacetylase Inhibitors Induce Growth Suppression and Cell Death in Human Rhabdomyosarcoma in Vitro Clin. Cancer Res., November 15, 2003; 9(15): 5749 - 5755. [Abstract] [Full Text] [PDF]

				L. Catley, E. Weisberg, Y.-T. Tai, P. Atadja, S. Remiszewski, T. Hideshima, N. Mitsiades, R. Shringarpure, R. LeBlanc, D. Chauhan, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma Blood, October 1, 2003; 102(7): 2615 - 2622. [Abstract] [Full Text] [PDF]

				C. L. Antos, T. A. McKinsey, M. Dreitz, L. M. Hollingsworth, C.-L. Zhang, K. Schreiber, H. Rindt, R. J. Gorczynski, and E. N. Olson Dose-dependent Blockade to Cardiomyocyte Hypertrophy by Histone Deacetylase Inhibitors J. Biol. Chem., August 1, 2003; 278(31): 28930 - 28937. [Abstract] [Full Text] [PDF]

				J. R. Davie Inhibition of Histone Deacetylase Activity by Butyrate J. Nutr., July 1, 2003; 133(7): 2485S - 2493. [Abstract] [Full Text] [PDF]

				L. M. Butler, X. Zhou, W.-S. Xu, H. I. Scher, R. A. Rifkind, P. A. Marks, and V. M. Richon The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin PNAS, September 3, 2002; 99(18): 11700 - 11705. [Abstract] [Full Text] [PDF]