The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth

Abstract Background Anaplastic thyroid cancer (ATC) remains refractory to available surgical and medical interventions. Histone deacetylase (HDAC) inhibitors are an emerging targeted therapy with antiproliferative activity in a variety of thyroid cancer cell lines. Thailandepsin A (TDP-A) is a novel...

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Published in:The Journal of surgical research 2014-07, Vol.190 (1), p.191-197
Main Authors: Weinlander, Eric, BA, Somnay, Yash, BS, Harrison, April D., BS, Wang, Cheng, PhD, Cheng, Yi-Qiang, PhD, Jaskula-Sztul, Renata, PhD, Yu, Xiao-Min, MD, PhD, Chen, Herbert, MD, FACS
Format: Article
Language:English
Subjects:
Anaplastic
Apoptosis - drug effects
Cell Cycle Checkpoints - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Depsipeptides - pharmacology
Dose-Response Relationship, Drug
Growth inhibition
HDAC inhibitor
Histone Deacetylase Inhibitors - pharmacology
Humans
Surgery
TDP-A
Thailandepsin A
Thyroid cancer
Thyroid Carcinoma, Anaplastic
Thyroid Neoplasms - drug therapy
Thyroid Neoplasms - pathology
Tumor Suppressor Protein p53 - analysis
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Summary:Abstract Background Anaplastic thyroid cancer (ATC) remains refractory to available surgical and medical interventions. Histone deacetylase (HDAC) inhibitors are an emerging targeted therapy with antiproliferative activity in a variety of thyroid cancer cell lines. Thailandepsin A (TDP-A) is a novel class I HDAC inhibitor whose efficacy remains largely unknown in ATC. Therefore, we aimed to characterize the effect of TDP-A on ATC. Methods Human-derived ATC cells were treated with TDP-A. IC50 was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid colorimetric assay, and cell proliferation was measured by viable cell count. Molecular mechanisms of cell growth inhibition were investigated by Western blot analysis of canonical apoptosis markers, intrinsic and extrinsic apoptosis regulators, and cell cycle regulatory proteins. Cell cycle staging was determined with propidium iodide flow cytometry. Results TDP-A dose- and time-dependently reduced cell proliferation. Increased cleavage of the apoptosis markers Caspase-9, Caspase-3, and poly adenosine diphosphate ribose polymerase were observed with TDP-A treatment. Levels of the intrinsic apoptosis pathway proteins BAD, Bcl-XL, and BAX remained unchanged. Importantly, the extrinsic apoptosis activator cleaved Caspase-8 increased dose-dependently, and the antiapoptotic proteins Survivin and Bcl-2 decreased. Among the cell cycle regulatory proteins, levels of CDK inhibitors p21/WAF1 and p27/KIP increased. Flow cytometry showed that ATC cells were arrested in G2/M phase with diminished S phase after TDP-A treatment. Conclusions TDP-A induces a notable dose- and time-dependent antiproliferative effect on ATC, which is mainly attributed to extrinsic apoptosis with concomitant cell cycle arrest. TDP-A therefore warrants further preclinical and clinical investigations.
ISSN:0022-4804
1095-8673
DOI:10.1016/j.jss.2014.02.042