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Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 9, pp 1507–1514

First Online: 04 July 2013Received: 24 April 2013Accepted: 19 June 2013DOI: 10.1007-s00432-013-1465-6

Cite this article as: Chan, D., Zheng, Y., Tyner, J.W. et al. J Cancer Res Clin Oncol 2013 139: 1507. doi:10.1007-s00432-013-1465-6

Abstract

PurposeAdvanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors HDACIs, belinostat and panobinostat, and a variety of tyrosine kinase inhibitors TKIs against a panel of nine human thyroid cancer cell lines.

MethodsThe anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay Calcusyn.

ResultsBelinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21, and PARP, and decreased levels of phosphorylated ERK and AKT Ser473. RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI pazopanib, motesanib, sorafenib and dasatinib were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro.

ConclusionsIn summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.

KeywordsHistone deacetylases Tyrosine kinase inhibitors Thyroid cancer Novel therapeutic approach Glenn D. Braunstein and H. Phillip Koeffler share last authorship.

Electronic supplementary materialThe online version of this article doi:10.1007-s00432-013-1465-6 contains supplementary material, which is available to authorized users.

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Author: Daniel Chan - Yun Zheng - Jeffrey W. Tyner - Wee Joo Chng - Wen Wen Chien - Sigal Gery - Geraldine Leong - Glenn D. Br

Source: https://link.springer.com/



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