Journal
CANCER RESEARCH
Volume 68, Issue 13, Pages 5370-5379Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-0511
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Funding
- NCI NIH HHS [5P30 CA016672-32] Funding Source: Medline
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Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-kappa B (NF-kappa B) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappa B activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappa B activation found in certain tumor cells. Suppression of NF-kappa B activation occurred through the inhibition of phosphorylation and degradation of I kappa B alpha by the inhibition of I kappa B kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappa B reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-kappa B-regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-alpha and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-kappa B activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent.
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