Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities resulting in either cell death or aneuploidy. Aurora kinases are often found overexpressed in several malignancies among which the anaplastic thyroid carcinoma (ATC). We previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In the present study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) have been analyzed on 4 human ATC cell lines (CAL-62, BHT-101, 8305C, 8505C). Both inhibitors reduced cell proliferation in a time- and dose-dependent manner, with IC50 ranges of 44.3-134.2 nM for MLN8237 and of 9.2-461.3 nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy evidenced that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152 treated cells, and in 2 out of 4 lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable to block anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but Aurora-A inhibition appears more effective in suppressing ATC cell proliferation and in inducing the apoptotic pathway.