Sanguinarine (pseudochelerythrine) is a potent inhibitor of NF-kappaB activation, IkappaBalpha phosphorylation, and degradation.
The nuclear factor NF-kappaB is a pleiotropic transcription factor whose activation results in inflammation, viral replication, and growth modulation. Due to its role in pathogenesis, NF-kappaB 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-kappaB activation. Treatment of human myeloid ML-1a cells with tumor necrosis factor rapidly activated NF-kappaB, this activation was completely suppressed by sanguinarine in a dose- and time-dependent manner. Sanguinarine did not inhibit the binding of NF-kappaB protein to the DNA but rather inhibited the pathway leading to NF-kappaB activation. The reversal of inhibitory effects of sanguinarine by reducing agents suggests a critical sulfhydryl group is involved in NF-kappaB activation. Sanguinarine blocked the tumor necrosis factor-induced phosphorylation and degradation of IkappaBalpha, an inhibitory subunit of NF-kappaB, and inhibited translocation of p65 subunit to the nucleus. As sanguinarine also inhibited NF-kappaB activation induced by interleukin-1, phorbol ester, and okadaic acid but not that activated by hydrogen peroxide or ceramide, the pathway leading to NF-kappaB activation is likely different for different inducers. Overall, our results demonstrate that sanguinarine is a potent suppressor of NF-kappaB activation and it acts at a step prior to IkappaBalpha phosphorylation.
Chaturvedi
M M
MM
Cytokine Research Section, Department of Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. aggarwal@utmdacc.mda.uth.tmc.edu
Kumar
A
A
Darnay
B G
BG
Chainy
G B
GB
Agarwal
S
S
Aggarwal
B B
BB
D000470:Alkaloids / Q000494:pharmacology*; D053119:Benzophenanthridines; D002451:Cell Compartmentation / Q000187:drug effects; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007546:Isoquinolines; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000470:Alkaloids; D053119:Benzophenanthridines; D002518:Ceramides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007546:Isoquinolines; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB; D019319:Okadaic Acid; C005705:sanguinarine; D006861:Hydrogen Peroxide; D000254:Sodium-Potassium-Exchanging ATPase; D013755:Tetradecanoylphorbol Acetate; D004229:Dithiothreitol