Aurora Kinases as Targets in Drug-Resistant Neuroblastoma Cells | Zendy

Martin Michaelis | Zendy; Florian Selt | Zendy; Florian Rothweiler | Zendy; Nadine Löschmann | Zendy; Benedikt Nüsse | Zendy; Wilhelm G. Dirks | Zendy; Richard Zehner | Zendy; Jindřich Činátl | Zendy

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Aurora Kinases as Targets in Drug-Resistant Neuroblastoma Cells

Author(s) -

Martin Michaelis,

Florian Selt,

Florian Rothweiler,

Nadine Löschmann,

Benedikt Nüsse,

Wilhelm G. Dirks,

Richard Zehner,

Jindřich Činátl

Publication year - 2014

Publication title -

plos one

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.99

H-Index - 332

ISSN - 1932-6203

DOI - 10.1371/journal.pone.0108758

Subject(s) - aurora kinase , aurora inhibitor , aurora a kinase , kinase , aurora b kinase , cancer research , neuroblastoma , chemistry , biology , microbiology and biotechnology , cell cycle , apoptosis , cell culture , biochemistry , cell , genetics , cell division , spindle apparatus

Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.

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