Induction of apoptosis by cyclo-oxygenase-2 inhibitor NS398 through a cytochrome C-dependent pathway in esophageal cancer cells.
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce tumor cells to undergo apoptosis in vitro. They have also shown cancer-preventive activity in vivo. The mechanism of their effects is, however, not well defined. We investigated the mechanism by which a new NSAID, NS398, induces apoptosis in esophageal cancer cell lines. NS398 decreased cell viability in 2 cyclo-oxygenase-2-positive (COX-2(+)) esophageal cancer cell lines but not in a COX-2(-) cell line. DNA fragmentation and TUNEL assays demonstrated that NS398 induced the 2 COX-2(+) cancer cell lines to undergo apoptosis. The percentage of apoptosis induced by NS398 was associated with the level of COX-2 expression. Further investigation showed that the cytochrome c pathway was responsible for NS398-induced apoptosis; i.e., cytochrome c was released from mitochondria, caspase-9 and caspase-3 were activated and finally poly(ADP-ribose)polymerase (PARP) was cleaved. Furthermore, the effect of NS398 was inhibited by the caspase inhibitor Z-DEVD-FMK and prostaglandin E(2). In contrast, bcl-2, bax, c-myc, Fas and Fas-ligand showed minor changes. Altogether, our data suggest that induction of apoptosis by NS398 is associated with COX-2 expression and occurs through the cytochrome c-dependent pathway, which sequentially activates caspase-9 and caspase-3 and cleaves PARP.
Li
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M
Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Wu
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Xu
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D017209:Apoptosis / Q000235:genetics; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009578:Nitrobenzenes / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003574:Cytochrome c Group; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011506:Proteins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D015232:Dinoprostone