Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells
Open Access
- 11 December 2008
- journal article
- Published by Springer Science and Business Media LLC in Journal of Translational Medicine
- Vol. 6 (1), 79
- https://doi.org/10.1186/1479-5876-6-79
Abstract
Background: A large percentage of patients with recurrent ovarian cancer develop resistance to the taxane class of chemotherapeutics. While mechanisms of resistance are being discovered, novel treatment options and a better understanding of disease resistance are sorely needed. The mitotic kinase Aurora-A directly regulates cellular processes targeted by the taxanes and is overexpressed in several malignancies, including ovarian cancer. Recent data has shown that overexpression of Aurora-A can confer resistance to the taxane paclitaxel.Methods: We used expression profiling of ovarian tumor samples to determine the most significantly overexpressed genes. In this study we sought to determine if chemical inhibition of the Aurora kinase family using VE-465 could synergize with paclitaxel to induce apoptosis in paclitaxel-resistant and sensitive ovarian cancer cells.Results: Aurora-A kinase and TPX2, an activator of Aurora-A, are two of the most significantly overexpressed genes in ovarian carcinomas. We show that inhibition of the Aurora kinases prevents phosphorylation of a mitotic marker and demonstrate a dose-dependent increase of apoptosis in treated ovarian cancer cells. We demonstrate at low doses that are specific to Aurora-A, VE-465 synergizes with paclitaxel to induce 4.5-fold greater apoptosis than paclitaxel alone in 1A9 cells. Higher doses are needed to induce apoptosis in paclitaxel-resistant PTX10 cells.Conclusion: Our results show that VE-465 is a potent killer of taxane resistant ovarian cancer cells and can synergize with paclitaxel at low doses. These data suggest patients whose tumors exhibit high Aurora-A expression may benefit from a combination therapy of taxanes and Aurora-A inhibition.Keywords
This publication has 59 references indexed in Scilit:
- Bora and the Kinase Aurora A Cooperatively Activate the Kinase Plk1 and Control Mitotic EntryScience, 2008
- Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL:In vitroandin vivostudiesCancer Science, 2008
- Evidence that p53-Mediated Cell-Cycle-Arrest Inhibits Chemotherapeutic Treatment of Ovarian CarcinomasPLOS ONE, 2007
- The BRCA1/BARD1 Heterodimer Modulates Ran-Dependent Mitotic Spindle AssemblyCell, 2006
- Dynamic localization and functional implications of Aurora-C kinase during male mouse meiosisDevelopmental Biology, 2006
- Aurora-A and an Interacting Activator, the LIM Protein Ajuba, Are Required for Mitotic Commitment in Human CellsCell, 2003
- Inhibition of Aurora B Kinase Blocks Chromosome Segregation, Overrides the Spindle Checkpoint, and Perturbs Microtubule Dynamics in MitosisCurrent Biology, 2002
- Drosophila Aurora-A Is Required for Centrosome Maturation and Actin-Dependent Asymmetric Protein Localization during MitosisCurrent Biology, 2002
- Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora KinasesMolecular and Cellular Biology, 2002
- A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancersThe EMBO Journal, 1998