Pirfenidone inhibits TGF-beta expression in malignant glioma cells.

Abstract

Due to its immunosuppressive properties, the cytokine transforming growth factor (TGF)-beta 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-beta2 protein levels in human glioma cell lines. This reduction in TGF-beta2 is biologically relevant since PFD treatment reduces the growth inhibition of TGF-beta-sensitive CCL-64 cells mediated by conditioned media of glioma cells. The downregulation of TGF-beta is mediated at multiple levels. PFD leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, PFD reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta 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-beta activity.

• Authors: Isabel Burghardt, Felix Tritschler, Christiane A Opitz, Brigitte Frank, Michael Weller, Wolfgang Wick
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 354 Issue 2 Pg. 542-7 (Mar 09 2007) ISSN: 0006-291X [Print] United States
• PMID: 17234158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Pyridones
• Transforming Growth Factor beta
• pirfenidone

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (drug therapy, metabolism)
• Humans
• Mink
• Pyridones (pharmacology)
• Transforming Growth Factor beta (antagonists & inhibitors, biosynthesis, genetics)