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Eriocalyxin B Inhibits Nuclear Factor-B Activation by Interfering with the Binding of Both p65 and p50 to the Response Element in a Noncompetitive Manner

Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut (C.-H.L., S.P.G., W.L., W.G., Y.-C.C.); and State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, People's Republic of China (H.-D.S.)

Nuclear factor-B (NF-B) has been recognized to play a critical role in cell survival and inflammatory processes. It has become a target for intense drug development for the treatment of cancer, inflammatory, and autoimmune diseases. Here, we describe a potent NF-B inhibitor, eriocalyxin B (Eri-B), an ent-kauranoid isolated from Isodon eriocalyx, an anti-inflammatory remedy. The presence of two ,-unsaturated ketones give this compound the uniqueness among the ent-kauranoids tested. Eri-B inhibited the NF-B transcriptional activity but not that of cAMP response element-binding protein. It suppressed the transcription of NF-B downstream gene products including cyclooxygenase-2 and inducible nitric-oxide synthase induced by tumor necrosis factor- or lipopolysaccharide in macrophages and hepatocarcinoma cells. Chromatin immunoprecipitation assay indicated that Eri-B selectively blocked the binding between NF-B and the response elements in vivo without affecting the nuclear translocation of the transcription factor. Down-regulation of the endogenous p65 protein sensitized the cells toward the action of the compound. Furthermore, in vitro binding assays suggested that Eri-B reversibly interfered with the binding of p65 and p50 subunits to the DNA in a noncompetitive manner. In summary, this study reveals the novel action of a potent NF-B inhibitor that could be potentially used for the treatment of a variety of NF-B-associated diseases. Modification of the structure of this class of compounds becomes the key to the control of the behavior of the compound against different cellular signaling pathways.

Address correspondence to: Dr. Yung-Chi Cheng, Department of Pharmacology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8066. E-mail: yccheng{at}yale.edu

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