Aurora kinases as targets in drug-resistant neuroblastoma cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 25268132.
- Also identified by DOI 10.1371/journal.pone.0108758 and PMC identifier 4182628.
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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.
Medical subject headings
- Antineoplastic Agents
- Aurora Kinase A
- Aurora Kinase B
- Azepines
- Gene Expression Regulation, Neoplastic
- Piperazines
- Protein Kinase Inhibitors
- Pyrimidines