N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-beta 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 fact or-beta (TGF-beta) are key biological features that contribute to the malig nant phenotype of hu man gliomas. Tranilast (N-[3,4-dimethoxycinnamoyl]-ant hranilic acid) is an anti-allergic compound used clinically to control atop ic and fibrotic disorders, These effects are attributed to the suppression of TGF-P, synthesis and interference with growth factor-mediated proliferat ion and migration of fibroblasts and vascular smooth muscle cells. Here, we show that tranilast inhibits DNA synthesis and proliferation of human mali gnant glioma cells and promotes p21 accumulation in the absence of cytotoxi city. 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) in tegrin expression at the cell surface but appear to involve inhibition of m atrix metalloproteinase-a expression and activity. Neither the tranilast-me diated inhibition of proliferation nor the inhibition of migration was coun teracted by supplementation with exogenous TGF-beta. Finally, tranilast adm inistered orally inhibited the growth of experimental 9L rat gliomas and re duced expression of TGF-beta, in vivo. We conclude that tranilast might be a useful therapeutic agent for the treatment of human malignant glioma beca use of a TGF-P-independent abrogation of the malignant phenotype of prolife ration, migration and invasiveness and because of the antagonism of TGF-bet a -associated immunosuppression. (C) 2001 Wiley-Liss, Inc.