Introduction:There is increasing evidence that Non Steroidal Anti-inflammatory Drugs (NSAIDs) have Cyclooxygenase-2 (COX-2) independent actions in cancer. These effects occur regardless of COX-2 expression and may be beneficial or detrimental. This study compared the actions of specific COX-2 inhibitors (Celecoxib, NS398) with that of OSU-03012, a celecoxib derivative, in pancreatic cancer.
Methods: A previous study confirmed that pancreatic cancer cell lines BxPC-3 and AsPC-1 have consistently high and negligible COX-2 expression, respectively. Proliferating cells were treated with NS398, celecoxib or OSU-03012 and LC50’s determined using MTT assay. Prostaglandin E2 (PGE2) and Vascular Endothelial Growth Factor (VEGF) production were measured by ELISA. Significance was calculated using unpaired t test.
Results: Each of the reagents had a concentration dependant effect on cell viability regardless of cellular COX-2. The LC50 for NS398 was >100μM and for Celecoxib >50μM. OSU-03012 was cytotoxic at 10μM in AsPC-1 cells and had a LC50 of 15-20μM in both cell lines. Of note, proliferating cells more susceptible than confluent (p<0.01). COX-2 was inhibited by 1μM Celecoxib or NS398 (p<0.001). PGE2 was moderately reduced by 10μM OSU-03012 (p<0.001). NS398 and OSU-03012 did not effect VEGF levels however it was increased 1.8 (AsPC-1) and 2.1 (BxPC-3) fold by 50μM Celecoxib (p<0.01).
Conclusion: Although high dose Celecoxib is cytotoxic to pancreatic cancer cells, it stimulates production of VEGF, a growth factor associated with worse prognosis. OSU-03012, a celecoxib derivative, has similar cytotoxicity but at lower, physiologically achievable concentrations without affecting VEGF. Thus OSU-03012 has exciting potential for pancreatic cancer therapy.