A novel copper complex of 3‐benzoyl‐α methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway

• Published in: International journal of cancer Vol. 120; no. 4; pp. 734 - 742
• Main Authors: Ahmed, Fakhara, Adsule, Shreelekha, Ali, Ashhar S., Banerjee, Sanjeev, Ali, Shadan, Kulkarni, Sudhir, Padhye, Subhash, Sarkar, Fazlul H
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.02.2007; Wiley-Liss
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Binding Sites; Biological and medical sciences; Cell Proliferation - drug effects; Copper - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; cyclooxygenase‐2; Dinoprostone - metabolism; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Humans; Immunoenzyme Techniques; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NSAIDS; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; pancreatic cancer cells; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Phenylacetates - chemistry; Polymerase Chain Reaction; prostaglandin E2; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Cells, Cultured - drug effects; Tumors; Antineoplastic agent; Human; Prostaglandin-endoperoxide synthase; Enzyme; cyclooxygenase-2; Enzyme inhibitor; Cyclooxygenase 2 inhibitor; Malignant tumor; In vitro; Biological activity; Ketoprofen; Non steroidal antiinflammatory agent; Cancerology; prostaglandin E2; Eicosanoid; NSAIDS; Pancreas cancer; Digestive diseases; Arylpropionic acid derivatives; Oxidoreductases; pancreatic cancer cells; Copper; Pancreatic disease
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22383

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 (PGE2) 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 IC50 of 10 μmol/L, which was lower than that of ketoprofen (IC50 = 35.4 μmol/L) and celecoxib (IC50 > 100 μmol/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 PGE2 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 PGE2 production. The authors also found a significant reduction of COX‐2 at the mRNA and protein levels together with downregulation of NF‐κB 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.