Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells

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Title: Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells
Author: Scharer, Christopher D. ; Laycock, Noelani ; Osunkoya, Adeboye O. ; Logani, Sanjay ; McDonald, John F. ; Benigno, Benedict B. ; Moreno, Carlos S.
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.
Description: © 2008 Scharer et al; licensee BioMed Central Ltd. The electronic version of this article is the complete one and can be found online at: DOI:10.1186/1479-5876-6-79
Type: Article
ISSN: 1479-5876
Citation: Christopher D. Scharer, Noelani Laycock, Adeboye O. Osunkoya, Sanjay Logani, John F. McDonald, Benedict B. Benigno, and Carlos S. Moreno, "Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells," Journal of Translational Medicine 2008, 6:79.
Date: 2008-12-11
Contributor: Georgia Institute of Technology. School of Biology
Emory University. Dept. of Pathology and Laboratory Medicine
Emory University. Program in Genetics and Molecular Biology
Georgia Institute of Technology. Ovarian Cancer Institute
Winship Cancer Institute of Emory University
Publisher: Georgia Institute of Technology
BioMed Central
Subject: Aurora-A inhibition
Taxane resistant ovarian cancer cells
Recurrent ovarian cancer

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