Sanguinarine (pseudochelerythrine) is a potent inhibitor of NF-κB activation, IκBα phosphorylation, and degradation

Abstract

The nuclear factor NF-κB is a pleiotropic transcription factor whose activation results in inflammation, viral replication, and growth modulation. Due to its role in pathogenesis, NF-κB is considered a key target for drug development. In the present report we show that sanguinarine (a benzophenanthridine alkaloid), a known anti-inflammatory agent, is a potent inhibitor of NF-κB activation. Treatment of human myeloid ML-1a cells with tumor necrosis factor rapidly activated NF-κB, this activation was completely suppressed by sanguinarine in a dose- and time-dependent manner. Sanguinarine did not inhibit the binding of NF-κB protein to the DNA but rather inhibited the pathway leading to NF-κB activation. The reversal of inhibitory effects of sanguinarine by reducing agents suggests a critical sulfhydryl group is involved in NF-κB activation. Sanguinarine blocked the tumor necrosis factor-induced phosphorylation and degradation of IκBα, an inhibitory subunit of NF-κB, and inhibited translocation of p65 subunit to the nucleus. As sanguinarine also inhibited NF-κB activation induced by interleukin-1, phorbol ester, and okadaic acid but not that activated by hydrogen peroxide or ceramide, the pathway leading to NF-κB activation is likely different for different inducers. Overall, our results demonstrate that sanguinarine is a potent suppressor of NF-κB activation and it acts at a step prior to IκBα phosphorylation.