title: Cyclooxygenase-2 inhibitors demonstrate anti-proliferative effects in oesophageal cancer cells by prostaglandin E(2)-independent mechanisms.
abstract: The incidence of oesophageal cancer (OC) has risen in recent decades, with survival rates remaining poor despite surgical treatment and adjuvant chemotherapy. Studies have reported cyclooxygenase-2 (COX-2) overexpression in OC and current evidence suggests NSAIDs have major potential for chemoprevention through COX-2 inhibition. However, several reports have questioned the specificity of these inhibitors, suggesting they may act through mechanisms other than COX-2. We evaluated the effects of specific COX-2 inhibitors, NS-398 and nimesulide, on cell lines of both histological types of OC. COX-2 protein expression varied in the cell lines and corresponded with levels of prostaglandin E(2) (PGE(2)) production. Following treatment with low concentrations of NS-398 (0.1 microM), PGE(2) production was reduced dramatically, indicating inhibition of COX-2 activity. Examination of cellular morphology, caspase-3 activity and mitochondrial membrane integrity found no major induction of apoptotic cell death at concentrations below 100 microM. Tumour cell proliferation was significantly reduced at high concentrations (50-100 microM) of both inhibitors over 6 days. Cellular responses were more evident in NS-398-treated adenocarcinoma cells. However, concentrations required to inhibit proliferation were up to 1000-fold higher than those needed to inhibit enzyme activity. Addition of exogenous PGE(2) to NS-398-treated adenocarcinoma cells failed to reverse the inhibitory effects, indicating PG and COX-2 independence. It remains possible that in vivo COX-2 is the primary target, as enzyme inhibition can be achieved at low concentrations, however, inhibition of proliferation is not the primary mechanism of their anti-tumour activity.
authors: Leslie C. Quick Laboratory, Cork Cancer Research Centre, 5th Floor, BioSciences Institute, University College Cork and Mercy University Hospital, Grenville Place, Cork, Ireland.
authors: B M
authors: BM
authors: Deasy
authors: G
authors: G
authors: O'Sullivan-Coyne
authors: T R
authors: TR
authors: O'Donovan
authors: S L
authors: SL
authors: McKenna
authors: G C
authors: GC
authors: O'Sullivan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects; D009578:Nitrobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D053148:Caspase 3; D015232:Dinoprostone; C012655:nimesulide