Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: inhibition of tumor angiogenesis with extensive tumor necrosis.
OBJECTIVE
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
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).


CONCLUSIONS
Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necrosis.
Kang
Khong Bee
KB
Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre, Singapore. dmskkb@nccs.com.sg
Wang
Ting Ting
TT
Woon
Chow Thai
CT
Cheah
Elizabeth S
ES
Moore
Xiao Lei
XL
Zhu
Congju
C
Wong
Meng Cheong
MC
D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011720:Pyrazoles / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects*; D013449:Sulfonamides / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D052246:Cyclooxygenase 2 Inhibitors; D009363:Neoplasm Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone