Abstract 1951: Inhibition of aurora kinase using VX-680 enhances the radiation response in glioma cells

Abstract

Abstract The central role of aurora kinases in cell cycle regulation coupled with overexpression of aurora A and B kinases in a wide variety of human malignancies that led to the development of pharmacological inhibitors of aurora kinases. New generations of aurora inhibitors, including VX-680, has been evaluated preclinically and are in phase I and II trials for the treatment of solid tumors and leukemia. In this study, we investigated the role of VX680, Aurora kinase inhibitor in malignant human glioma cells with different p53 statuses as well as cytotoxicity of glioma cells to irradiation. VX-680 inhibits aurora A and B kinases and cell proliferation with nanomolar to low micromolar potency. Endoreduplication, the re-replication of DNA in the absence of mitotic division, ultimately results in polyploidy and inhibition of cell proliferation. VX680 treatment led to an increase in the number of multinucleated cells and the ratios of G2/M phase in p53-mutant (LN229) and p53-deleted cells (LNZ308), but minimal in p53-wild type (A172) glioma cells. FACS analysis revealed that the increase in nuclear size correlated with polyploidization, reaching a >16 DNA content on day 2. During mitosis, the cells rounded normally, condensed their chromosomes on a metaphase-like plate. Our results demonstrate that pretreating cells with VX-680 prior to ionizing radiation led to an enhancement of radiation -induced apoptosis. Accordingly, our results suggested that Aurora kinase inhibition followed by irradiation increases in the appearance of multinucleated cells and increase apoptosis, and this treatment may become a potential therapy against malignant human gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1951. doi:10.1158/1538-7445.AM2011-1951