title: Non-steroidal anti-inflammatory drugs inhibit cellular proliferation and upregulate cyclooxygenase-2 protein expression in endometrial cancer cells.
abstract: We determined the effects of several non-steroidal anti-inflammatory drugs (NSAIDs), aspirin (acetylsalicylic acid, ASA), indomethacin and a cyclooxygenase-2 (COX-2)-selective inhibitor (NS398), on cellular proliferation and regulation of COX-2 protein expression in endometrial cancer cells in vitro, and investigated their modes of action. All three NSAIDs markedly inhibited the proliferation of Ishikawa, HEC-1A and AN3CA endometrial cancer cell lines in a time- and concentration-dependent manner. ASA and indomethacin triggered apoptosis in cells of all three lines through release of cytosolic cytochrome c, activation of caspase-9 and-3, and cleavage of poly(ADP-ribose) polymerase (PARP), but NS398 induced minimal apoptosis only in Ishikawa cells. ASA altered the cell cycle distribution, with G2/M phase accumulation of cells, and induced overexpression of Ki-67 protein. Both ASA and indomethacin reduced the protein levels of Bcl-2 and Bcl-xl, but upregulated those of Bax and Bcl-xs. COX-2 protein expression and PGE(2) production were upregulated by ASA and indomethacin in all three cell lines. However, NS398 did not alter COX-2 protein expression or PGE(2) production in these cells. These results indicate that NSAIDs inhibit proliferation of endometrial cancer cells independently of the reduction of COX-2 protein expression. A cytochrome c-dependent apoptotic pathway and/or cell cycle arrest may contribute to the inhibitory effects of these NSAIDs.
authors.affiliation: Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu 501-1194.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Gao
authors.forename: Kenji
authors.initials: K
authors.lastname: Niwa
authors.forename: Wenshu
authors.initials: W
authors.lastname: Sun
authors.forename: Masao
authors.initials: M
authors.lastname: Takemura
authors.forename: Zenglin
authors.initials: Z
authors.lastname: Lian
authors.forename: Kyoko
authors.initials: K
authors.lastname: Onogi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.forename: Hideki
authors.initials: H
authors.lastname: Mori
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Tamaya
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D007213:Indomethacin