Anti-NF-kappaB and anti-inflammatory activities of synthetic isothiocyanates: effect of chemical structures and cellular signaling.
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.
Prawan
Auemduan
A
Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
Saw
Constance Lay Lay
CL
Khor
Tin Oo
TO
Keum
Young-Sam
YS
Yu
Siwang
S
Hu
Longqin
L
Kong
Ah-Ng
AN
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
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