title: 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 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.
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Eric
authors.initials: E
authors.lastname: Weinlander
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Yash
authors.initials: Y
authors.lastname: Somnay
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: April D
authors.initials: AD
authors.lastname: Harrison
authors.affiliation: Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin; UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas.
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Cheng
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Electronic address: yux@surgery.wisc.edu.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Electronic address: chen@surgery.wisc.edu.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D016159:Tumor Suppressor Protein p53; C574693:thailandepsin A
keywords: Anaplastic; Growth inhibition; HDAC inhibitor; TDP-A; Thailandepsin A; Thyroid cancer