Celecoxib inhibits invasion and metastasis via a cyclooxygenase 2-independent mechanism in an in vitro model of Ewing sarcoma.
BACKGROUND
Previously, we reported that celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, prevented lung metastases but did not affect tumor growth in a model of Ewing sarcoma. Cyclooxygenase-2 inhibition has been proposed as an antimetastatic strategy. The mechanism of action remains unclear.


METHODS
Ewing sarcoma cells were suspended in a soluble basement membrane extract (Cultrex; Trevigen, Inc, Gaithersburg, MD) and supplemented with celecoxib or with rofecoxib, a second COX-2 inhibitor, above a filter. Controls received solvent. After 48 hours, the cells that invaded through the basement membrane and filter were stained and counted. The assay was repeated with the addition of 500-nM prostaglandin E2 (PGE(2)).


RESULTS
Invasion was significantly decreased in the celecoxib groups compared with the control. The addition of PGE(2) did not overcome celecoxib inhibition. Rofecoxib did not significantly affect invasion compared with control either with or without PGE(2).


CONCLUSIONS
Celecoxib significantly inhibits invasion of Ewing sarcoma cells in vitro. Prostaglandin E2, a downstream product of COX-2, did not reverse in vitro inhibition, suggesting that celecoxib acts through a COX-2-independent mechanism. This is further supported by the failure of rofecoxib to inhibit invasion despite more selectively inhibiting COX-2.
Division of Pediatric Surgery, Steven and Alexandra Cohen Children's Medical Center of New York, North Shore-Long Island Jewish Health System, New Hyde Park, NY 11040, USA.
Meade
M
Barlow
Morris
M
Edelman
Richard D
RD
Glick
Bettie M
BM
Steinberg
Samuel Z
SZ
Soffer
D001485:Basement Membrane; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology*; D000068579:Celecoxib; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D009363:Neoplasm Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone