title: Inhibition by costunolide of phorbol ester-induced transcriptional activation of inducible nitric oxide synthase gene in a human monocyte cell line THP-1.
abstract: Costunolide, the predominant sesquiterpene lactone in Saussureae radix, has been reported to exhibit potent chemopreventive effects on carcinogenesis. Effects of costunolide on cellular activation induced by a tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) were investigated using a reporter gene assay which was designed to reflect the promoter activity of the inducible nitric oxide synthase (iNOS) gene in a human monocyte cell line THP-1. iNOS promoter-dependent reporter gene activity was significantly increased by TPA, and the TPA-induced increase of the reporter gene activity was efficiently reduced by costunolide, with an IC50 of approximately 2 microM. The addition of sulfhydryl (SH) compounds effectively abrogated the inhibitory effects of costunolide, suggesting the involvement of its reactivity with SH groups of target proteins and/or thiol-depleting property. The present findings may further explain the cancer-preventive property of costunolide.
authors.affiliation: Department of Oriental Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. kfukuda@cc.gifu-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.forename: S
authors.initials: S
authors.lastname: Akao
authors.forename: Y
authors.initials: Y
authors.lastname: Ohno
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010703:Phorbol Esters / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D015533:Transcriptional Activation; D014810:Vitamin E / Q000494:pharmacology; D007783:Lactones
chemical_list: D016588:Anticarcinogenic Agents; D001205:Ascorbic Acid; D005707:Gallic Acid; D008156:Luciferases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D010703:Phorbol Esters; D011493:Protein Kinase C; D012717:Sesquiterpenes; D013438:Sulfhydryl Compounds; D013755:Tetradecanoylphorbol Acetate; D014810:Vitamin E; C002602:costunolide; D007783:Lactones; C496319:NOS2 protein, human; C005854:3,4,5-trimethoxybenzoic acid