Indirubins Decrease Glioma Invasion by Blocking Migratory Phenotypes in Both the Tumor and Stromal Endothelial Cell Compartments
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio 43210, USA.Cancer Research (Impact Factor: 9.33). 06/2011; 71(16):5374-80. DOI: 10.1158/0008-5472.CAN-10-3026
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 · 2.88 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 · 4.08 Impact Factor
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ABSTRACT: Extensive research over the past several years has indicated a close association between chronic inflammation and chronic diseases. Chronic inflammation has now been shown to be involved in the onset and development of numerous chronic diseases, including cancer, neurological diseases, cardiovascular diseases, hypertension, blood pressure, atherosclerosis, diabetes, obesity, respiratory disorders, musculoskeletal disorders, gastro-intestinal disorders, and autoimmune disorders. An interesting fact that has emerged over the years is that most chronic diseases are caused by lifestyle factors such as stress, toxicants, tobacco, alcohol, infectious agents, and radiation. How chronic inflammation contributes to chronic diseases has also been elucidated over the years. The discovery of transcription factors such as NF-κB, STAT3, AP-1, NRF2, PPAR-γ, β-catenin/Wnt, HIF-1α, and Hedgehog, as well as the signalling molecules regulating these transcription factors has provided a molecular link between chronic inflammation and chronic diseases. Thus agents that can modulate the expression of these transcription factors might be useful against chronic diseases. Because of limited efficacy and high toxicity, mono-targeted anti-inflammatory agents have little effect against chronic diseases. Agents derived from natural sources called botanicals have gained particular attention for their anti-inflammatory activity, not only because they are multi-targeted but also because they are safe, cost effective, and readily available. How transcription factors contribute to the development of chronic diseases is the focus of this review. Additionally, we also describe various botanicals and the inflammatory transcription factors that they modulate.01/2012: pages 57-132;
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