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Departments of 1 Surgery, 2 Pathology, 3 Pharmacology and Cancer Biology, and 4 Neurobiology, 5 Division of Neurology, Duke University Medical Center, Durham, North Carolina; and 6 GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania
Requests for reprints: Jeremy N. Rich, Division of Neurology, Duke University Medical Center, P.O. Box 2900, Durham, NC 27710. Phone: 919-681-1693; Fax: 919-684-6514. E-mail: rich0001{at}mc.duke.edu
Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-ß2 ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-ß in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-ß 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-ß signaling, with decreased TGF-ß–mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-ß-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-ß–mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-ß receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1/ 5/04; revised 3/18/04; accepted 4/12/04.
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