Enhancement of Glioblastoma Radioresponse by a Selective COX-2 Inhibitor Celecoxib: Inhibition of Tumor Angiogenesis With Extensive Tumor Necrosis

Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):888-96. doi: 10.1016/j.ijrobp.2006.09.055.

Abstract

Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis.

Methods and materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of mice intracranially implanted with U-87MG cells and treated with celecoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by von Williebrand's factor (vWF) immunohistochemical staining.

Results: Celecoxib (4 and 30 microM; 24, 48, and 72 h) enhanced U-87MG cell radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celecoxib alone and when combined with irradiation. In vivo, median survival of control mice intracranially implanted with U-87MG cells was 18 days. Celecoxib (100 mg/kg/day, 2 weeks) significantly extended median survival of irradiated mice (24 Gy total) from 34 to 41 days, with extensive tumor necrosis [24.5 +/- 8.6% of tumor region, compared with irradiation alone (2.7 +/- 1.8%)]. Tumor microvascular density was significantly reduced in combined celecoxib and irradiated tumors (52.5 +/- 2.9 microvessels per mm2 tumor region), compared with irradiated tumors alone (65.4 +/- 4.0 microvessels per mm2).

Conclusion: Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necrosis.

MeSH terms

  • Angiopoietin-1 / metabolism
  • Angiopoietin-2 / metabolism
  • Animals
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy*
  • Celecoxib
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / therapeutic use*
  • Dinoprostone / metabolism
  • Glioblastoma / blood supply
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / radiotherapy*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Necrosis
  • Neoplasm Proteins / metabolism
  • Neovascularization, Pathologic / prevention & control*
  • Pyrazoles / therapeutic use*
  • Radiation Tolerance / drug effects*
  • Sulfonamides / therapeutic use*
  • Tumor Stem Cell Assay
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiopoietin-1
  • Angiopoietin-2
  • Cyclooxygenase 2 Inhibitors
  • Neoplasm Proteins
  • Pyrazoles
  • Sulfonamides
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone