Preclinical testing of selective Aurora kinase inhibitors on a XXXX -derived cell line.

@entity5700 @entity36013 @entity5 @entity7433 @entity1890 @entity875 @entity16511 @entity16513 @entity259
UNASSIGNED: Deregulated expression of the @entity875 ( @entity875 , B, and C) is thought to be involved in cell malignant transformation and genomic instability in several @entity5 types. Over the last decade, a number of small-molecule inhibitors of @entity875 have been developed, which have proved to efficiently restrain malignant cell growth and @entity7433 . Regarding @entity259 ( @entity259 ), we previously showed the efficacy of a pan-Aurora kinase inhibitor ( @entity16513 ) in impairing growth and survival of the @entity259 -derived cell line TT. In the present study, we sought to establish if one of the @entity875 might represent a preferential target for @entity259 therapy. The effects of selective inhibitors of @entity875 ( @entity1890 ) and @entity16511 ( @entity36013 ) were analyzed on TT cell proliferation, apoptosis, cell cycle, and ploidy. The two inhibitors reduced TT cell proliferation in a time- and dose-dependent manner, with IC50 of 19.0      2.4  nM for @entity1890 and 401.6      44.1  nM for @entity36013 . Immunofluorescence experiments confirmed that @entity36013 inhibited phosphorylation of histone H3 (Ser10) by @entity16511 , while it did not affect @entity875 autophosphorylation. @entity1890 inhibited @entity875 autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Cytofluorimetry experiments showed that both inhibitors induced accumulation of cells in G2/M phase and increased the subG0/G1 fraction and @entity5700 . Finally, both inhibitors triggered apoptosis. We demonstrated that inhibition of either @entity875 or @entity16511 has antiproliferative effects on TT cells, and thus it would be worthwhile to further investigate the therapeutical potential of Aurora kinase inhibitors in @entity259 treatment.
