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 Fantin, V. R. Articles by Richon, V. M. Search for Related Content PubMed PubMed Citation Articles by Fantin, V. R. Articles by Richon, V. M.

Mechanisms of Resistance to Histone Deacetylase Inhibitors and Their Therapeutic Implications

Authors' Affiliation: Merck Research Laboratories, Boston, Massachusetts

Requests for reprints: Victoria M. Richon, Cancer Biology and Therapeutics, Merck Research Laboratories, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115. Phone: 617-992-2044; Fax: 617-992-2412; E-mail: victoria_richon{at}merck.com.

Abstract

Histone deacetylase inhibitors (HDI) are a promising new approach to the treatment of cancer. HDIs have been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of transformed cell lines; inhibit tumor growth in animal models; and show antitumor activity in clinical trials. Vorinostat, which has shown clinical responses in 30% of patients with advanced cutaneous T-cell lymphoma, is the first HDI approved for the treatment of cancer, and it is currently being evaluated in other indications. A better understanding of the molecular determinants of resistance to HDIs may provide the basis for therapeutic combinations with improved clinical efficacy. Poor response to treatment could be linked to systemic factors like pharmacokinetics or to tumor-specific factors both at the level of the malignant cells (tumor intrinsic) or the tumor microenvironment. This review focuses on the tumor intrinsic mechanisms of drug resistance (excluding mechanism of acquired resistance due to chronic exposure). In particular, attention is given to selected mechanisms that are relevant across chemical classes of HDIs and that can aid in the design of rational combination strategies.

This article has been cited by other articles:

				K. N. Bhalla Combined Therapy with Agents Targeted against Deregulated Epigenetic Mechanisms in Cancer Am. Assoc. Cancer Res. Educ. Book, April 18, 2009; 2009(1): 233 - 236. [Full Text] [PDF]

				R. M. Balliet, G. Chen, C. J. Gallagher, R. W. Dellinger, D. Sun, and P. Lazarus Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype Cancer Res., April 1, 2009; 69(7): 2981 - 2989. [Abstract] [Full Text] [PDF]

				W. Fiskus, R. Rao, P. Fernandez, B. Herger, Y. Yang, J. Chen, R. Kolhe, A. Mandawat, Y. Wang, R. Joshi, et al. Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells Blood, October 1, 2008; 112(7): 2896 - 2905. [Abstract] [Full Text] [PDF]

				H. Nian, B. Delage, J. T. Pinto, and R. H. Dashwood Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter Carcinogenesis, September 1, 2008; 29(9): 1816 - 1824. [Abstract] [Full Text] [PDF]