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.
| Author: | Martin MichaelisORCiDGND, Florian Selt, Florian RothweilerGND, Nadine LöschmannGND, Benedikt Nüsse, Wilhelm G. Dirks, Richard ZehnerORCiDGND, Jindrich CinatlORCiDGND |
|---|---|
| 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): |  Creative Commons - Namensnennung 4.0 |
