N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-β release and reduces migration and invasiveness of human malignant glioma cells

Extensive infiltration of normal brain tissue and suppression of anti-tumor immune surveillance mediated by molecules such as transforming growth factor-beta (TGF-beta) are key biological features that contribute to the malignant phenotype of hu man gliomas. Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) is an anti-allergic compound used clinically to control atopic and fibrotic disorders, These effects are attributed to the suppression of TGF-P, synthesis and interference with growth factor-mediated proliferation and migration of fibroblasts and vascular smooth muscle cells. Here, we show that tranilast inhibits DNA synthesis and proliferation of human malignant glioma cells and promotes p21 accumulation in the absence of cytotoxicity. Further, tranilast reduces the release of TGF-beta, and TGF-beta, by glioma cells and inhibits migration, chemotactic responses and invasiveness. These effects are not associated with a reduction of alpha (v)beta (3) integrin expression at the cell surface but appear to involve inhibition of matrix metalloproteinase-a expression and activity. Neither the tranilast-mediated inhibition of proliferation nor the inhibition of migration was counteracted by supplementation with exogenous TGF-beta. Finally, tranilast administered orally inhibited the growth of experimental 9L rat gliomas and reduced expression of TGF-beta, in vivo. We conclude that tranilast might be a useful therapeutic agent for the treatment of human malignant glioma because of a TGF-P-independent abrogation of the malignant phenotype of proliferation, migration and invasiveness and because of the antagonism of TGF-beta -associated immunosuppression. (C) 2001 Wiley-Liss, Inc.