title: Novel histone deacetylase inhibitors in the treatment of thyroid cancer.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. cmitsiades@partners.org
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Poulaki
authors.forename: Ciaran
authors.initials: C
authors.lastname: McMullan
authors.forename: Joseph
authors.initials: J
authors.lastname: Negri
authors.forename: Galinos
authors.initials: G
authors.lastname: Fanourakis
authors.forename: Athina
authors.initials: A
authors.lastname: Goudopoulou
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Marks
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000473:pathology*; D016923:Cell Death; D002934:Cinnamates / Q000494:pharmacology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C111238:carboxycinnamic acid bishydroxamide; D000077337:Vorinostat