Aurora-A inhibition offers a novel therapy effective against intracranial glioblastoma.

Cancer research (2014-08-12)
James R Van Brocklyn, Jeffrey Wojton, Walter H Meisen, David A Kellough, Jeffery A Ecsedy, Balveen Kaur, Norman L Lehman

Glioblastoma remains a devastating disease for which novel therapies are urgently needed. Here, we report that the Aurora-A kinase inhibitor alisertib exhibits potent efficacy against glioblastoma neurosphere tumor stem-like cells in vitro and in vivo. Many glioblastoma neurosphere cells treated with alisertib for short periods undergo apoptosis, although some regain proliferative activity upon drug removal. Extended treatment, however, results in complete and irreversible loss of tumor cell proliferation. Moreover, alisertib caused glioblastoma neurosphere cells to partially differentiate and enter senescence. These effects were also observed in glioma cells treated with the Aurora-A inhibitor TC-A2317 or anti-Aurora-A siRNA. Furthermore, alisertib extended median survival of mice bearing intracranial human glioblastoma neurosphere tumor xenografts. Alisertib exerted similar effects on glioblastoma neurosphere cells in vivo and resulted in markedly reduced activated phosphoThr288Aurora-A and increased abnormal mitoses and cellular ploidy, consistent with on-target activity. Our results offer preclinical proof-of-concept for alisertib as a new therapeutic for glioma treatment.

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Hydrogen peroxide solution, 30 % (w/w) in H2O, contains stabilizer
Hydrogen peroxide solution, 3%, suitable for microbiology
Hydrogen peroxide solution, contains ~200 ppm acetanilide as stabilizer, 3 wt. % in H2O
Hydrogen peroxide solution, contains inhibitor, 30 wt. % in H2O, meets USP testing specifications
TC-A2317 hydrochloride, ≥98% (HPLC)