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...

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Published in:	PloS one Vol. 9; no. 9; p. e108758
Main Authors:	Michaelis, Martin, Selt, Florian, Rothweiler, Florian, Löschmann, Nadine, Nüsse, Benedikt, Dirks, Wilhelm G, Zehner, Richard, Cinatl, Jr, Jindrich
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 30-09-2014 Public Library of Science (PLoS)
Subjects:	Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects ATP Binding Cassette Transporter, Subfamily B - genetics ATP Binding Cassette Transporter, Subfamily B - metabolism Aurora kinase Aurora Kinase A - antagonists & inhibitors Aurora Kinase A - genetics Aurora Kinase A - metabolism Aurora Kinase B - antagonists & inhibitors Aurora Kinase B - genetics Aurora Kinase B - metabolism Azepines - pharmacology Binding sites Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Breast cancer Cell cycle Cell Cycle Checkpoints - drug effects Cell lines Cell Proliferation - drug effects Drug resistance Drug Resistance, Neoplasm Drug Synergism Enzyme inhibitors Gene Expression Regulation, Neoplastic Histone H3 Histones - genetics Histones - metabolism Humans Imidazoles - pharmacology Inhibitors Kinases Leukemia MDM2 protein Medicine and Health Sciences Neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - genetics Neuroblastoma - metabolism Neuroblastoma - pathology Neuroblastoma cells p53 Protein Phosphorylation Phosphorylation - drug effects Phosphotransferases Piperazines - pharmacology Primary Cell Culture Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-mdm2 - genetics Proto-Oncogene Proteins c-mdm2 - metabolism Pyrimidines - pharmacology Signal Transduction Signaling Substrate inhibition Tumor proteins Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism United Kingdom > UK Germany
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Summary:	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.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: MM FS FR NL BN WGD RZ JC. Performed the experiments: MM FS FR NL BN RZ JC. Analyzed the data: MM FS FR NL BN WGD RZ JC. Contributed reagents/materials/analysis tools: MM WGD RZ JC. Wrote the paper: MM JC. Current address: Deutsches Krebsforschungszentrum (DKFZ), Klinische Kooperationseinheit Pädiatrische Onkologie (G340) and Pädiatrie III, Zentrum für Kinder- und Jugendmedizin, Heidelberg, Germany Current address: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, United Kingdom
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0108758