Inhibitory effect of pirfenidone on glioblastoma cell lines: Implications for treatment of neurofibromatosis

Sunil Krishnan, Jennie M. Goble, Lori A. Frederick, C. David James, Joon H. Uhm, Scott H Kaufmann, Dusica Babovic-Vuksanovic

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by diverse cutaneous, neurological, skeletal, and neoplastic manifestations with no standard drug treatment options available. Pirfenidone is an oral agent undergoing clinical investigation in NF1, where its antifibrotic properties are used to target the fibrotic component of plexiform neurofibromas. The effect of pirfenidone on other cells in these complex tumors is unknown. We studied the effects of pirfenidone on malignant glioma cell lines to take advantage of easily cultured and rapidly growing cells with similar biologic properties to NF1-derived tumors. On a standardized MTS assay, pirfenidone showed dose-dependent inhibition of cell proliferation. Using a tritiated thymidine assay, dose-dependent DNA synthesis inhibition was seen as early as 2 hours after treatment. Gelatin and casein zymography showed inhibition of matrix metallopeptidase 2 (MMP-2) activity at a time point when no inhibition of proliferation was noted. Western blotting with an antibody to epidermal growth factor receptor (EGFR) phosphotyrosine residues documented dose-dependent inhibition of EGFR phosphorylation. An 8-hour measurement of apoptosis using propidium iodide flow cytometry revealed a large sub-G0 population of cells upon treatment of cells with 10 mg/mL of pirfenidone. These results suggest that pirfenidone has antitumor effects on malignant gliomas, which is partly mediated through inhibition of EGFR phosphorylation.

Original languageEnglish (US)
Pages (from-to)58-68
Number of pages11
JournalJournal of Applied Research
Volume7
Issue number1
StatePublished - 2007

Fingerprint

Neurofibromatoses
Glioblastoma
Cell Line
Neurofibromatosis 1
Epidermal Growth Factor Receptor
Glioma
Plexiform Neurofibroma
Phosphorylation
Phosphotyrosine
Propidium
Metalloproteases
Gelatin
Caseins
Thymidine
pirfenidone
Neoplasms
Flow Cytometry
Western Blotting
Cell Proliferation
Apoptosis

Keywords

  • Epidermal growth factor receptor
  • Glioblastoma
  • Glioma
  • Neurofibromatosis type I
  • Pirfenidone

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology

Cite this

Inhibitory effect of pirfenidone on glioblastoma cell lines : Implications for treatment of neurofibromatosis. / Krishnan, Sunil; Goble, Jennie M.; Frederick, Lori A.; David James, C.; Uhm, Joon H.; Kaufmann, Scott H; Babovic-Vuksanovic, Dusica.

In: Journal of Applied Research, Vol. 7, No. 1, 2007, p. 58-68.

Research output: Contribution to journalArticle

Krishnan, Sunil ; Goble, Jennie M. ; Frederick, Lori A. ; David James, C. ; Uhm, Joon H. ; Kaufmann, Scott H ; Babovic-Vuksanovic, Dusica. / Inhibitory effect of pirfenidone on glioblastoma cell lines : Implications for treatment of neurofibromatosis. In: Journal of Applied Research. 2007 ; Vol. 7, No. 1. pp. 58-68.
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