TY - JOUR
T1 - Anti-NF-κB and anti-inflammatory activities of synthetic isothiocyanates
T2 - Effect of chemical structures and cellular signaling
AU - Prawan, Auemduan
AU - Saw, Constance Lay Lay
AU - Khor, Tin Oo
AU - Keum, Young Sam
AU - Yu, Siwang
AU - Hu, Longqin
AU - Kong, Ah Ng
PY - 2009/5/15
Y1 - 2009/5/15
N2 - 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.
AB - 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.
KW - Anti-inflammatory response
KW - Cancer chemopreventive compounds
KW - Isothiocyanates
KW - NF-κB
KW - Nrf2
UR - http://www.scopus.com/inward/record.url?scp=62549085979&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2008.12.014
DO - 10.1016/j.cbi.2008.12.014
M3 - Article
C2 - 19159619
AN - SCOPUS:62549085979
SN - 0009-2797
VL - 179
SP - 202
EP - 211
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 2-3
ER -