Abstract
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-beta(2) ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-beta in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-beta receptor, on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGF-beta signaling, with decreased TGF-beta-mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-beta-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-beta-mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-beta receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Activin Receptors, Type I / antagonists & inhibitors*
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Activin Receptors, Type I / metabolism
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Benzamides / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects*
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Cell Proliferation / drug effects
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DNA-Binding Proteins / metabolism
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Dioxoles / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects
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Glioma / drug therapy
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Glioma / pathology*
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Humans
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / metabolism
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Smad Proteins
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Trans-Activators / metabolism
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Transcription, Genetic / drug effects
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / pharmacology
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Benzamides
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DNA-Binding Proteins
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Dioxoles
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Trans-Activators
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I