Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Aurora Kinase A / antagonists & inhibitors*
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Aurora Kinase A / genetics
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Aurora Kinase A / metabolism
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Aurora Kinase B / antagonists & inhibitors*
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Aurora Kinase B / genetics
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Aurora Kinase B / metabolism
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Azepines / pharmacology*
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Brain Neoplasms / drug therapy
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Cycle Checkpoints / drug effects
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm
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Drug Synergism
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Gene Expression Regulation, Neoplastic*
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Histones / genetics
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Histones / metabolism
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Humans
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Imidazoles / pharmacology
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Neuroblastoma / drug therapy
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Neuroblastoma / genetics
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Phosphorylation / drug effects
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Piperazines / pharmacology*
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Primary Cell Culture
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Pyrimidines / pharmacology*
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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Antineoplastic Agents
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Azepines
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Histones
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Imidazoles
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MLN 8237
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Tumor Suppressor Protein p53
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tozasertib
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nutlin 3
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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AURKA protein, human
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AURKB protein, human
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Aurora Kinase A
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Aurora Kinase B