SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility

Abstract

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-β2 ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-β in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-β 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-β signaling, with decreased TGF-β-mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-β-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-β-mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-β receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility. Copyright © 2004 American Association for Cancer Research.