Novel histone deacetylase inhibitors in thetreatment of thyroid cancer Journal Article


Authors: Mitsiades, C. S.; Poulaki, V.; McMullan, C.; Negri, J.; Fanourakis, G.; Goudopoulou, A.; Richon, V. M.; Marks, P. A.; Mitsiades, N.
Article Title: Novel histone deacetylase inhibitors in thetreatment 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/orapoptosis 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-xL 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 clAP-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. © 2005 American Association for Cancer Research.
Keywords: controlled study; protein expression; unclassified drug; human cell; histone deacetylase inhibitor; antineoplastic agents; cell death; protein bcl 2; apoptosis; enzyme degradation; down-regulation; caspase 3; cytotoxicity; drug effect; tumor cells, cultured; protein bcl xl; cancer inhibition; gene expression regulation, neoplastic; death receptor; carcinoma; vorinostat; hydroxamic acids; down regulation; caspase 8; caspase 9; thyroid cancer; thyroid neoplasms; protein p21; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; histone deacetylases; acetylation; cinnamates; receptor upregulation; protein bax; flice inhibitory protein; caspase 7; drug sensitization; caspase 2; 3 carboxycinnamic acid bis hydroxamide
Journal Title: Clinical Cancer Research
Volume: 11
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2005-05-15
Start Page: 3958
End Page: 3965
Language: English
DOI: 10.1158/1078-0432.ccr-03-0776
PUBMED: 15897598
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 46" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus"
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  1. Paul Marks
    183 Marks
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