Ethyl 3′,4′,5′-trimethoxythionocinnamate modulates NF-κB and Nrf2 transcription factors

Recently, we identified a novel cinnamate analog, ethyl 3′,4′,5′-trimethoxythionocinnamate (ETMTC) as a potent inhibitor of cell adhesion molecules (CAMs), such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. However, its mechanism of action has not been elucidated so far. Since, nuclear factor-kappa B (NF-κB) is the major transcription factor involved in the regulation of ICAM-1, VCAM-1 and E-selectin expression, we determined the status of NF-κB activation in ETMTC treated human endothelial cells. Here, we demonstrate that ETMTC inhibits TNF-α-induced nuclear translocation and activation of NF-κB by inhibiting phosphorylation and degradation of IκBα. The inhibition of IκBα phosphorylation and degradation by ETMTC was found to be due to its ability to inhibit IκB kinase activity. In addition, oxidative stress is known to regulate NF-κB activation through TNF-α signaling cascade, therefore, we examined the effect of ETMTC on TNF-α-induced reactive oxygen species generation. We observed that ETMTC significantly inhibits TNF-α-induced reactive oxygen species generation in endothelial cells. To further elucidate the anti-oxidant potential of ETMTC, we examined its effect on induction of anti-oxidant genes viz. glutamate-cysteine ligase, modifier subunit (GCLM), heme oxygenase-1 (HO1) and NAD (P)H:quinone oxidoreductase 1 (NQO1) in human bronchial epithelial cells. Interestingly, ETMTC significantly induces the anti-oxidant genes viz. GCLM, HO1 and NQO1 by activating nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Thus, ETMTC could be useful towards developing potent anti-inflammatory molecules.