Abstract LB-293: Indirubins decrease glioma growth and invasion in vivo: A novel treatment paradigm combining antimigratory and antiangiogenic effects

Abstract

Abstract The invasive nature of gliomas is a major obstacle to their effective treatment. We demonstrated in a recent report that lithium blocks glioma cell migration and that this involved the inhibition of glycogen synthase kinase-3 (GSK-3). Here we report that treatment of glioma cells with GSK-3 inhibitors of the indirubin family leads to a potent and specific blockade of glioma cell migration. Indirubins inhibited GSK-3 to a greater extent than lithium in glioma cells as assessed by ß-catenin TCF/LEF luciferase reporter assays and were effective at much lower concentrations than other GSK-3 inhibitors so far tested. When examined in intracranial xenograft models in nude mice, 6-bromo-indirubin acetoxime (BIA) led to a significant reduction of invasion of normal, both in terms of diffuse invasion around the tumor, and the number of tumor foci. Interestingly treatment with BIA also led to decreased tumor proliferation and significantly improved survival of tumor-bearing animals. Histological examination of tumors showed a substantial decrease in blood vessel density in tumors. Finally we showed that indirubins block motility of endothelial cells in vitro, and also cause increased production of anti-angiogenic proteins in BIA treated glioma cells. This data suggests that anti-invasive glioma therapy with indirubins, and potentially other GSK-3 inhibitors, not only inhibits invasion of tumor cells, but also blocks angiogenesis providing a novel treatment paradigm for invasive gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-293.