Radiosensitization of human glioma cells by cyclooxygenase-2 (COX-2) inhibition: independent on COX-2 expression and dependent on the COX-2 inhibitor and sequence of administration.
OBJECTIVE
Patients with a malignant glioma have a very poor prognosis. Cyclooxygenase-2 (COX-2) protein is regularly upregulated in gliomas and might be a potential therapeutic target. The effects of three selective COX-2 inhibitors were studied on three human glioma cell lines.


METHODS
The selective COX-2 inhibitors NS-398, Celecoxib and Meloxicam and three human glioma cell lines (D384, U251 and U87) were used. Cell growth was assessed by a proliferation assay, the interaction with radiation (0 - 6 Gy) was studied using the clonogenic assay and cell cycle distribution was determined by FACS (fluorescence-activated cell sorting) analysis.


RESULTS
All COX-2 inhibitors reduced proliferation of the glioma cell lines irrespective of their COX-2 expression level. Incubation with 200 microM NS-398 24 h before radiation enhanced radiation-induced cell death of D384 cells and 750 microM Meloxicam resulted in radiosensitization of D384 and U87 cells. No radiosensitization was observed with COX-2 inhibitor administration after radiotherapy. Treatment of D384 with NS-398 (200 microM) or Celecoxib (50 microM) and U87 with NS-398 (200 microM) after radiation resulted even in radioprotection.


CONCLUSIONS
Effectiveness of COX-2 inhibitors on cell proliferation and radio-enhancement was independent of COX-2 protein expression. The sequence of COX-2 inhibitor addition and irradiation is very important.
Kuipers
Gitta K
GK
Department of Radiation Oncology, division Radiobiology, VU University Medical Center, Amsterdam, The Netherlands. gk.kuipers@vumc.nl
Slotman
Ben J
BJ
Wedekind
Laurine E
LE
Stoter
T Rianne
TR
Berg
Jaap van den
Jv
Sminia
Peter
P
Lafleur
M Vincent M
MV
D000068579:Celecoxib; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology; D006801:Humans; D000077239:Meloxicam; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013843:Thiazines / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D011720:Pyrazoles; D011837:Radiation-Protective Agents; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D000077239:Meloxicam