A novel copper complex of 3-benzoyl-alpha methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway.
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 micromol/L, which was lower than that of ketoprofen (IC(50) = 35.4 micromol/L) and celecoxib (IC(50) > 100 micromol/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-kappaB 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.
Ahmed
Fakhara
F
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Adsule
Shreelekha
S
Ali
Ashhar S
AS
Banerjee
Sanjeev
S
Ali
Shadan
S
Kulkarni
Sudhir
S
Padhye
Subhash
S
Sarkar
Fazlul H
FH
D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010648:Phenylacetates / Q000737:chemistry; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D052246:Cyclooxygenase 2 Inhibitors; C519539:FPA-306; D008565:Membrane Proteins; D016328:NF-kappa B; D009942:Organometallic Compounds; D010648:Phenylacetates; D019253:Proto-Oncogene Proteins c-bcl-2; D003300:Copper; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C025136:phenylacetic acid; D015232:Dinoprostone