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

Eric Weinlander, Yash Somnay, April D. Harrison, Cheng Wang, Yi Qiang Cheng, Renata Jaskula-Sztul, Xiao Min Yu, Herbert Chen

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21 Scopus citations

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.

Original languageEnglish
Pages (from-to)191-197
Number of pages7
JournalJournal of Surgical Research
Volume190
Issue number1
DOIs
StatePublished - Jul 2014

Keywords

  • Anaplastic
  • Growth inhibition
  • HDAC inhibitor
  • TDP-A
  • Thailandepsin A
  • Thyroid cancer

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    Weinlander, E., Somnay, Y., Harrison, A. D., Wang, C., Cheng, Y. Q., Jaskula-Sztul, R., Yu, X. M., & Chen, H. (2014). The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth. Journal of Surgical Research, 190(1), 191-197. https://doi.org/10.1016/j.jss.2014.02.042