Abstract
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-kappaB (NF-kappaB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappaB activation found in certain tumor cells. Suppression of NF-kappaB activation occurred through the inhibition of phosphorylation and degradation of IkappaBalpha by the inhibition of IkappaB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappaB 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-kappaB-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-kappaB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent.
Highlights
Almost 80% of the world population cannot afford modern medicine
Carcinogenic, and inflammatory effects and various gene products modulated by berberine are regulated by the transcription factor nuclear factor-nB (NF-nB), we postulated that this pathway plays a major role in the action of berberine
We investigated the effect of berberine on constitutively active NF-nB and on that activated by various carcinogens and inflammatory stimuli, on NF-nB–regulated gene expression, on apoptosis induced by cytokines and chemotherapeutic agents, and on invasion
Summary
Almost 80% of the world population cannot afford modern medicine. Traditional medicine is inexpensive but generally neitherNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Berberine has been shown to suppress the growth of a wide variety of tumor cells including leukemia [2], melanoma [3], epidermoid carcinoma [4], hepatoma [5], oral carcinoma [6], glioblastoma [7], prostate carcinoma [8], and gastric carcinoma [9]. Animal studies have shown that berberine can suppress chemicalinduced carcinogenesis [10], tumor promotion [11], and tumor invasion [12] It is a radiosensitzer of tumor cells but not of normal cells [13]. How berberine mediates these effects is not fully understood, but its ability to modulate Mcl-1 [6], Bcl-xL [5], cyclooxygenase (COX)-2 [6], MDR [14], tumor necrosis factor (TNF)-a and IL-6 [15], iNOS [16], IL-12 [17], intercellular adhesion molecule-1 and ELAM-1 expression [12], MCP-1 and CINC-1 [18], cyclin D1 [19], activator protein Carcinogenic, and inflammatory effects and various gene products (such as TNF-a, IL-6, COX-2, adhesion molecules, cyclin D1, and MDR) modulated by berberine are regulated by the transcription factor nuclear factor-nB (NF-nB), we postulated that this pathway plays a major role in the action of berberine
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