SANGUINARINE (PSEUDOCHELERYTHRINE) IS A POTENT INHIBITOR OF NP-KAPPA-B ACTIVATION, I-KAPPA-B-ALPHA PHOSPHORYLATION, AND DEGRADATION

The nuclear factor NF-kappa B is a pleiotropic transcription factor wh ose activation results in inflammation, viral replication, and growth modulation. Due to its role in pathogenesis, NF-kappa KB is considered a key target for drug development. In the present report we show that sanguinarine (a benzophenanthridine alkaloid), a known anti-inflammat ory agent, is a potent inhibitor of NF-kappa B activation. Treatment o f human myeloid ML-1a cells with tumor necrosis factor rapidly activat ed NF-kappa B this activation was completely suppressed by sanguinarin e in a dose- and time-dependent manner. Sanguinarine did not inhibit t he binding of NF-kappa B protein to the DNA but rather inhibited the p athway leading to NF-kappa B activation. The reversal of inhibitory ef fects of sanguinarine by reducing agents suggests a critical sulfhydry l group is involved in NF-kappa B activation. Sanguinarine blocked the tumor necrosis factor-induced phosphorylation and degradation of I ka ppa B alpha, an inhibitory subunit of NF-kappa B, and inhibited transl ocation of p65 subunit to the nucleus. As sanguinarine also inhibited NF-kappa B activation induced by interleukin-1, phorbol ester, and oka daic acid but not that activated by hydrogen peroxide or ceramide, the pathway leading to NF-kappa B activation is likely different for diff erent inducers, Overall, our results demonstrate that sanguinarine is a potent suppressor of NF-kappa B activation and it acts at a step pri or to I kappa B alpha phosphorylation.