Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX-2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX-2 enzyme and its metabolic product prostaglandin E2 (PGE 2 ) in PC. Here the authors report the synthesis and biological activity of a novel COX-2 inhibitor, FPA-306, and its effects on PC cells with different levels of COX-2 expression. Using MTT assay, the authors found a significant growth inhibition of BxPC-3 cells treated by FPA-306 with an IC 50 of 10 lmol/ L, which was lower than that of ketoprofen (IC 50 5 35.4 lmol/L) and celecoxib (IC 50 > 100 lmol/L). There was no such effect found in MIAPaCa cell line, which does not express COX-2. The authors also found dose dependent reduction in cell survival and induction of apoptosis by FPA-306 treatment in BxPC-3 cells but not in MIAPaCa cells. These results were correlated with apoptosis data and secreted PGE 2 levels. The molecular modeling of FPA-306 in the COX-2 active site showed that FPA-306 is potentially able to inhibit the activity of enzyme by blocking the active site, thereby resulting in decreased PGE 2 production. The authors also found a significant reduction of COX-2 at the mRNA and protein levels together with downregulation of NF-jB DNA binding activity and its downstream genes, Bcl-2 and survivin. These results suggest that FPA-306 is an effective and potent agent in inhibiting the growth of PC cells. ' 2006 Wiley-Liss, Inc.Key words: pancreatic cancer cells; cyclooxygenase-2; NSAIDS; prostaglandin E 2 Pancreatic cancer (PC) is the fourth leading cause of cancer related death in the United States. An estimated 33,730 individuals will be diagnosed with PC in the year of 2006, with an almost similar incidence rate among males and females. 1 PC is relatively resistant to all currently available therapeutic approaches including radiotherapy and chemotherapy. Palliative care is the only option because most of the patients are also not suitable for surgery at the time of diagnosis. Thus, delayed diagnosis partly due to indolent nature of pancreatic tumor progression and lack of effective therapy results in limited survival.From a mechanistic point of view, several molecular pathways have been identified such as Ras-Raf-MEK-ERK, PI3K/Akt and NF-jB pathway that are believed to be important in the development, progression and metastasis of PC. In addition, the involvement of cyclooxygenase (COX) and lipoxygenase family of enzymes in the development and progression of PC has been appreciated recently. 2 The COX family of enzymes catalyzes the ratelimiting step in conversion of arachidonic acid into prostaglandins. 3 Three isoforms of COX enzyme have been reported-COX-1, COX-2 and COX-3. 4 COX-1 is constitutively expressed in many tissues where it serves as house keeping gene whereas COX-2 is an inducible enzyme that is rapidly transcribed, perhaps regulated by NF-jB and other transcription factor...