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Novel Histone Deacetylase Inhibitors in the Treatment of Thyroid Cancer

Authors' Affiliations: ¹ Department of Medical Oncology, Dana-Farber Cancer Institute; ² Department of Medicine, Beth Israel Deaconess Medical Center and ³ Massachusetts Eye and Ear Infirmary, Harvard Medical School; ⁴ Merck Research Laboratories, Boston, Massachusetts; ⁵ Department of Pathology, University of Athens, Athens, Greece; and ⁶ Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Constantine S. Mitsiades, Department of MedicalOncology, Dana-Farber Cancer Institute, Mayer Building, Room M557, 44 BinneyStreet, Boston, MA 02115. Phone: 617-632-1962; Fax: 617-812-7701; E-mail: cmitsiades{at}partners.orgcmitsiades{at}netscape.net

Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-x_L expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type–specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.

Key Words: Thyroid cancer • HDAC • SAHA

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