Ethyl 3′,4′,5′-trimethoxythionocinnarnate '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-kappa B) is the major transcription factor involved in the regulation of ICAM-1, VCAM-1 and E-selectin expression, we determined the status of NF-kappa B activation in ETMTC treated human endothelial cells. Here, we demonstrate that ETMTC inhibits TNF-alpha-induced nuclear translocation and activation of NF-kappa B by inhibiting phosphorylation and degradation of I kappa B alpha. The inhibition of I kappa B alpha phosphorylation and degradation by ETMTC was found to be due to its ability to inhibit I kappa B kinase activity. In addition, oxidative stress is known to regulate NF-kappa B activation through TNF-alpha signaling cascade, therefore, we examined the effect of ETMTC on TNF-alpha-induced reactive oxygen species generation. We observed that ETMTC significantly inhibits TNF-alpha-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. (C) 2012 Elsevier B.V. All rights reserved.