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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0108758&type=printable |
| _version_ | 1826587308305940480 |
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| author | Martin Michaelis Florian Selt Florian Rothweiler Nadine Löschmann Benedikt Nüsse Wilhelm G Dirks Richard Zehner Jindrich Cinatl |
| author_facet | Martin Michaelis Florian Selt Florian Rothweiler Nadine Löschmann Benedikt Nüsse Wilhelm G Dirks Richard Zehner Jindrich Cinatl |
| author_sort | Martin Michaelis |
| collection | DOAJ |
| description | 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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| format | Article |
| id | doaj.art-b551dba222e04115998820e0d2ac3df4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-14T16:23:22Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b551dba222e04115998820e0d2ac3df42025-02-22T05:32:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0199e10875810.1371/journal.pone.0108758Aurora kinases as targets in drug-resistant neuroblastoma cells.Martin MichaelisFlorian SeltFlorian RothweilerNadine LöschmannBenedikt NüsseWilhelm G DirksRichard ZehnerJindrich CinatlAurora 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0108758&type=printable |
| spellingShingle | Martin Michaelis Florian Selt Florian Rothweiler Nadine Löschmann Benedikt Nüsse Wilhelm G Dirks Richard Zehner Jindrich Cinatl Aurora kinases as targets in drug-resistant neuroblastoma cells. PLoS ONE |
| title | Aurora kinases as targets in drug-resistant neuroblastoma cells. |
| title_full | Aurora kinases as targets in drug-resistant neuroblastoma cells. |
| title_fullStr | Aurora kinases as targets in drug-resistant neuroblastoma cells. |
| title_full_unstemmed | Aurora kinases as targets in drug-resistant neuroblastoma cells. |
| title_short | Aurora kinases as targets in drug-resistant neuroblastoma cells. |
| title_sort | aurora kinases as targets in drug resistant neuroblastoma cells |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0108758&type=printable |
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