Induction of apoptosis by cyclo-oxygenase-2 inhibitor NS398 through a cytochromeC-dependent pathway in esophageal cancer cells

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Abstract
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 E2. 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.