Pirfenidone inhibits TGF-beta expression in malignant glioma cells.
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.
Burghardt
Isabel
I
Laboratory of Molecular Neuro-Oncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strasse 3, D-72076, Tübingen, Germany.
Tritschler
Felix
F
Opitz
Christiane A
CA
Frank
Brigitte
B
Weller
Michael
M
Wick
Wolfgang
W
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008907:Mink; D011728:Pyridones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics
D000970:Antineoplastic Agents; D011728:Pyridones; D016212:Transforming Growth Factor beta; C093844:pirfenidone