Pirfenidone inhibits TGF-β expression in malignant glioma cells

Due to its immunosuppressive properties, the cytokine transforming growth factor (TGF)-β has become a promising target in the experimental treatment of human malignant gliomas. Here, we report that the antifibrotic drug 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone, PFD) elicits growth-inhibitory effects and reduces TGF-β2 protein levels in human glioma cell lines. This reduction in TGF-β2 is biologically relevant since PFD treatment reduces the growth inhibition of TGF-β-sensitive CCL-64 cells mediated by conditioned media of glioma cells. The downregulation of TGF-β is mediated at multiple levels. PFD leads to a reduction of TGF-β2 mRNA levels and of the mature TGF-β2 protein due to decreased expression and direct inhibition of the TGF-β pro-protein convertase furin. In addition, PFD reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-β target gene and furin substrate involved in carcinogenesis. These data define PFD or PFD-related agents as promising agents for human cancers associated with enhanced TGF-β activity.