NS 398 radiosensitizes an HNSCC cell line by possibly inhibiting radiation-induced expression of COX-2.
OBJECTIVE
Cyclooxygenase-2 (COX-2) protein is frequently elevated in squamous cell carcinoma of the head and neck (HNSCC). The aim of this study was to determine if COX-2 inhibitors have radiosensitizing effects in HNSCC and understand the mechanism by which this occurs.


METHODS
The radiosensitizing effects of a selective COX-2 inhibitor, NS398, on a HNSCC cell line HEp3, were determined using clonogenic survival assay. Cells were pretreated with the dose of NS398 at which 50% growth inhibition occurred (IC(50)) and then irradiated. COX-2 protein and mRNA were then determined in the presence and absence of NS398.


RESULTS
NS398 significantly decreased (p < 0.0001) the calculated survival fraction (SF) for all radiation doses (0.79 to 0.41 at 2 Gy). A significant increase in COX-2 protein of 2.8 fold for 2 Gy and 3.5 fold for 6 Gy was noted 48 h after radiation. Interestingly, the upregulation of COX-2 protein with radiation was suppressed when cells were pretreated with NS398. Quantitative reverse transcriptase polymerase chain reaction showed no significant corresponding increase in COX-2 mRNA at 48 h with ionizing radiation.


CONCLUSIONS
The radiosensitizing effect of NS398 could be due to inhibition of radiation-induced COX-2 upregulation by this drug. NS398, known as an inhibitor of COX-2 enzyme activity, down-regulated COX-2 protein expression, which may indicate that NS398 can act upstream of COX-2, and this change appears to be post-transcriptional.
Amirghahari
Nazanin
N
Department of Otolaryngology/Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Harrison
Lynn
L
Smith
Melanie
M
Rong
Xiaohua
X
Naumann
Ilka
I
Ampil
Fred
F
Shi
Runhua
R
Glass
Jonathan
J
Nathan
Cherie Ann O
CO
D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000532:radiotherapy*; D045744:Cell Line, Tumor / Q000528:radiation effects; D002470:Cell Survival; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000532:radiotherapy*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009578:Nitrobenzenes; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases