title: Induction of apoptosis by JTE-522, a specific cyclooxygenase-2 inhibitor, in human gastric cancer cell lines.
abstract: An increased expression of cyclooxygenase (COX)-2 has been observed in various cancers including gastric cancer. Although specific COX-2 inhibitors have a chemopreventive effect on colon cancer, their molecular mechanisms remain unclear. To clarify these mechanisms, we investigated the effects of JTE-522, a newly developed COX-2-specific inhibitor, on gastric cancer cell lines (MKN28 and MKN45). The baseline levels of COX-2 expression were higher in MKN45 than in MKN28. JTE-522 obviously suppressed the levels of COX-2 mRNA, COX-2 protein and PGE2 at a dose of 250 microM in both cancer cells. Apoptosis was induced at 24 hours after treatment with JTE-522 (250 microM) in both cancer cells. To determine the mechanisms of apoptosis induction by JTE-522, the time course of the cell cycle and the apoptosis-related protein levels were examined. An increase in the G1 phase and a decrease in the S phase were observed prior to apoptosis. Moreover, an increase of c-myc protein and a decrease of bcl-2 protein were observed in both cells treated with JTE-522. These findings suggested that JTE-522 could induce apoptosis by blocking the cell cycle, enhancing c-myc expression and diminishing bcl-2 expression. JTE-522 also suppressed proliferation activity in both cell lines. These effects of JTE-522 were more dramatic in MKN45 than in MKN28. Since JTE-522 strongly suppresses cell growth by inducing apoptosis in gastric cancer cell lines, it may therefore serve as a chemopreventive agent.
authors.affiliation: Department of Surgery I and Microbiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan. k2uefu@med.email.ne.jp
authors.forename: K
authors.initials: K
authors.lastname: Uefuji
authors.forename: T
authors.initials: T
authors.lastname: Ichikura
authors.forename: N
authors.initials: N
authors.lastname: Shinomiya
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010080:Oxazoles / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D016196:S Phase / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D016588:Anticarcinogenic Agents; D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human