Abstract LB-391: Aurora kinase inhibitor AT9283 potently inhibits the proliferation and migration of medulloblastoma cells

Abstract

Abstract Aurora kinases play an important role in regulating cell mitotic division. It has been found that they are over expressed in many human cancers, and decreased expression in either Aurora kinase A or B levels lead to cell apoptosis. It has been suggested that Aurora kinase inhibitors might be an attractive molecular target of anticancer therapy. AT9283, a multi-targeted kinase inhibitor with potent activity against both Aurora kinases A and B, is currently being evaluated in clinical trails in patients with advanced hematological malignancies including AML. However to date, this compound has not been evaluated in medulloblastoma, one of the most common malignant brain tumors in children. In this study, AT9283 was investigated in a panel of human medulloblastoma cell lines (DAOY and D556) and the SmoA1 transgenic mouse model of medulloblastoma cells (PS125) to assess its ability to inhibit medulloblastoma cell survival, growth and migration. Western blotting demonstrated significant inhibition of both Aurora kinases A and B in each cell type by AT9283. MTT assay demonstrated that AT9283 significantly inhibited cell growth and proliferation in a dose-dependent manner in all 3 cell lines. Furthermore, the compound potently reduced phospho-histone H3 levels, and induced caspase-3 and cleaved PARP in all cells. AT9283 treatment at concentrations as low as 0.01–0.05μM significantly inhibited cell migration, as demonstrated by the Scratch assay without affecting caspase-3 induction, cleaved PARP or phospho-histone H3 levels. Thus taken together, our results indicate that AT983 has a dual effect on inhibiting cell growth and migration in medulloblastoma cells, suggesting it may be a valuable therapy in medulloblastoma treatment and warrants further preclinical in vivo investigation in this disease model. 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 LB-391. doi:10.1158/1538-7445.AM2011-LB-391