Many cancer chemopreventive agents have been associated with lower cancer risk by suppressing nuclear factor-κB (NF-κB) 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-κB 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-κB and the inflammatory response to bacterial lipopolysaccharide (LPS) were assessed. The synthetic ITC analogs suppressed NF-κB-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-κB 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-1β, IL-6 and TNF-α) were reduced by ITCs, and correlated with the downregulation of NF-κB signaling pathways. Immunoblotting showed that ITCs suppressed LPS-induced phosphorylation and degradation of IκBα and decreased nuclear translocation of p65. In parallel, ITCs suppressed the phosphorylation of IκB kinase α/β (IKKα/β). Taken together, our findings provide the possibility that synthetic ITC analogs might have promising cancer chemopreventive potential, based on their stronger anti-NF-κB and anti-inflammatory activities, than the natural ITCs.
All Science Journal Classification (ASJC) codes
- Anti-inflammatory response
- Cancer chemopreventive compounds