Cyclooxygenase-2 inhibitor NS398 enhances antitumor effect of irradiation on hormone refractory human prostate carcinoma cells.
OBJECTIVE
We examined the potential therapeutic effect of NS398, a selective cyclooxygenase-2 (COX-2) inhibitor, combined with irradiation on human prostate adenocarcinoma DU145 cells.


METHODS
The effect on tumor growth, proliferation testing and clonogenic survival was determined to evaluate its antitumor effect when exposed to NS398 or combined with irradiation. Immunoblotting analyses were done to detect the expression of COX-2, nuclear factor-kappaB p50 and Rel A p65 because evidence suggested a biological association of COX-2 with alterations in these markers. Reverse transcriptase-polymerase chain reaction was also performed to show its effect on the transcription level of COX-2.


RESULTS
Exposure of DU145 cells to NS398 alone suppressed proliferation in a dose and time dependent manner. Examination of the NS398 effect on the radiation response showed marked enhancement of radiosensitivity. Western blot indicated that NS398 down-regulated the expression of COX-2, nuclear factor-kappaB, p50 and Rel A p65, whereas the effect was more pronounced when combined with irradiation. Reverse transcriptase-polymerase chain reaction showed that the NS398 antitumor effect was associated with COX-2 transcription inhibition. Importantly COX-2 expression was enhanced by irradiation but this phenomenon was abolished when cells were exposed to NS398. Inhibition of tumor growth in animal model was observed when mice were treated with NS398 alone and irradiation alone, and this effect was maximal when treated with NS398 and irradiation.


CONCLUSIONS
These results suggest that NS398 could be used as a potential therapeutic agent combined with irradiation for prostate adenocarcinoma.
Wen
Bixiu
B
UPRES EA No. 27-10, Radiosensibilité des tumeurs et des tissues sains, Institut Gustave Roussy, 94805 Villejuif Cedex, France.
Deutsch
Eric
E
Eschwege
Pascal
P
De Crevoisier
Renaud
R
Nasr
Elie
E
Eschwege
François
F
Bourhis
Jean
J
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D016328:NF-kappa B / Q000235:genetics; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases