Indirubins Decrease Glioma Invasion by Blocking Migratory Phenotypes in Both the Tumor and Stromal Endothelial Cell Compartments
ABSTRACT Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that β-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in glioma-bearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer.
- World Neurosurgery 11/2011; 80(3-4). DOI:10.1016/j.wneu.2011.10.003 · 2.42 Impact Factor
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ABSTRACT: Glycogen synthase kinase-3 (GSK-3) is central to multiple intracellular pathways including those activated by Wnt/β-catenin, Sonic Hedgehog, Notch, growth factor/RTK, and G protein-coupled receptor signals. All of these signals importantly contribute to neural development. Early attention on GSK-3 signaling in neural development centered on the regulation of neuronal polarity using in vitro paradigms. However, recent creation of appropriate genetic models has demonstrated the importance of GSK-3 to multiple aspects of neural development including neural progenitor self-renewal, neurogenesis, neuronal migration, neural differentiation, and synaptic development.Frontiers in Molecular Neuroscience 11/2011; 4:44. DOI:10.3389/fnmol.2011.00044
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ABSTRACT: INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. AREAS COVERED: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. EXPERT OPINION: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients.Expert Opinion on Investigational Drugs 06/2012; 21(9):1391-415. DOI:10.1517/13543784.2012.694425 · 5.43 Impact Factor