Aurora kinases as targets in drug-resistant neuroblastoma cells

  • 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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Metadaten
Author:Martin MichaelisORCiDGND, Florian Selt, Florian RothweilerGND, Nadine Löschmann, Benedikt Nüsse, Wilhelm G. Dirks, Richard ZehnerGND, Jindrich CinatlORCiD
URN:urn:nbn:de:hebis:30:3-351010
DOI:https://doi.org/10.1371/journal.pone.0108758
ISSN:1932-6203
Parent Title (English):PLoS One
Publisher:PLoS
Place of publication:Lawrence, Kan.
Document Type:Article
Language:English
Date of Publication (online):2014/09/30
Date of first Publication:2014/09/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/10/17
Volume:9
Issue:(9):e108758
Page Number:9
Note:
Copyright: © 2014 Michaelis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS-PPN:366248332
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0