title: Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines.
abstract: OBJECTIVE
  Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated.
  
  
  METHODS
  The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar.
  
  
  RESULTS
  Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC(50) comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines.
  
  
  CONCLUSIONS
  Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Baldini
authors.forename: S
authors.initials: S
authors.lastname: Sorrenti
authors.forename: E
authors.initials: E
authors.lastname: D'Armiento
authors.forename: E
authors.initials: E
authors.lastname: Guaitoli
authors.forename: S
authors.initials: S
authors.lastname: Morrone
authors.forename: V
authors.initials: V
authors.lastname: D'Andrea
authors.forename: L
authors.initials: L
authors.lastname: Gnessi
authors.forename: C
authors.initials: C
authors.lastname: Moretti
authors.forename: A
authors.initials: A
authors.lastname: Antonelli
authors.forename: A
authors.initials: A
authors.lastname: Catania
authors.forename: E
authors.initials: E
authors.lastname: De Antoni
authors.forename: S
authors.initials: S
authors.lastname: Ulisse
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008698:Mesylates; D010671:Phenylurea Compounds / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D008698:Mesylates; D010671:Phenylurea Compounds; C532454:SNS 314; D013844:Thiazoles