title: Anti-NF-kappaB and anti-inflammatory activities of synthetic isothiocyanates: effect of chemical structures and cellular signaling.
abstract: Many cancer chemopreventive agents have been associated with lower cancer risk by suppressing nuclear factor-kappaB (NF-kappaB) signaling pathways, which subsequently leads to attenuated pro-inflammatory mediators and activities. Of the natural compounds, the isothiocyanates (ITCs) found in cruciferous vegetables have received particular attention because of their potential anti-cancer effects. However, limited studies regarding the influence of ITCs structure on NF-kappaB transactivation and anti-inflammatory action are reported. In the present study, the anti-inflammatory potential of ten structurally divergent synthetic ITCs were evaluated in HT-29-N9 human colon cancer cells and RAW 264.7 murine macrophages. The effect of ITCs on the basal transcriptional activation of NF-kappaB and the inflammatory response to bacterial lipopolysaccharide (LPS) were assessed. The synthetic ITC analogs suppressed NF-kappaB-mediated pro-inflammatory gene transcription. Among the ITC analogs, tetrahydrofurfuryl isothiocyanate, methyl-3-isothiocyanatopropionate, 3-morpholinopropyl isothiocyanate and 3,4-methyelendioxybenzyl isothiocyanate showed stronger NF-kappaB inhibition as compared to the parent compound, phenylethyl isothiocyanate (PEITC). Molecular analysis revealed that several of the pro-inflammatory mediators and cytokines (iNOS, COX-2, IL-1beta, IL-6 and TNF-alpha) were reduced by ITCs, and correlated with the downregulation of NF-kappaB signaling pathways. Immunoblotting showed that ITCs suppressed LPS-induced phosphorylation and degradation of IkappaB alpha and decreased nuclear translocation of p65. In parallel, ITCs suppressed the phosphorylation of IkappaB kinase alpha/beta (IKKalpha/beta). Taken together, our findings provide the possibility that synthetic ITC analogs might have promising cancer chemopreventive potential, based on their stronger anti-NF-kappaB and anti-inflammatory activities, than the natural ITCs.
authors.affiliation: Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: Auemduan
authors.initials: A
authors.lastname: Prawan
authors.forename: Constance Lay Lay
authors.initials: CL
authors.lastname: Saw
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Keum
authors.forename: Siwang
authors.initials: S
authors.lastname: Yu
authors.forename: Longqin
authors.initials: L
authors.lastname: Hu
authors.forename: Ah-Ng
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D017879:Isothiocyanates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017879:Isothiocyanates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; C037152:isothiocyanic acid; D009569:Nitric Oxide; D008156:Luciferases; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone