SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility
2004; American Association for Cancer Research; Volume: 3; Issue: 6 Linguagem: Inglês
10.1158/1535-7163.737.3.6
ISSN1538-8514
AutoresMark D. Hjelmeland, Anita B. Hjelmeland, Sith Sathornsumetee, Elizabeth D. Reese, Michael H. Herbstreith, Nicholas J. Laping, Henry S. Friedman, Darell D. Bigner, Xiao‐Fan Wang, Jeremy N. Rich,
Tópico(s)Angiogenesis and VEGF in Cancer
ResumoAbstract 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.
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