Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines.

Abstract

OBJECTIVES:

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.

MATERIALS AND 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: E Baldini, S Sorrenti, E D'Armiento, E Guaitoli, S Morrone, V D'Andrea, L Gnessi, C Moretti, A Antonelli, A Catania, E De Antoni, S Ulisse
• Journal: La Clinica terapeutica (Clin Ter) Vol. 163 Issue 5 Pg. e307-13 ( 2012) ISSN: 1972-6007 [Electronic] Italy
• PMID: 23099978 (Publication Type: Journal Article)

Chemical References

• Mesylates
• Phenylurea Compounds
• SNS 314
• Thiazoles

Topics

• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Humans
• Mesylates
• Phenylurea Compounds (pharmacology)
• Thiazoles (pharmacology)
• Thyroid Carcinoma, Anaplastic
• Thyroid Neoplasms (pathology)
• Tumor Cells, Cultured (drug effects)