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Novel Mechanism of Inhibition of Nuclear Factor-B DNA-Binding Activity by Diterpenoids Isolated from Isodon rubescens

Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut (C.-H.L., S.P.G., W.L., 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 (Q.-B.H., H.-D.S.)

The development of specific inhibitors that can block nuclear factor-B (NF-B) activation is an approach for the treatment of cancer, autoimmune, and inflammatory diseases. Several diterpenoids, oridonin, ponicidin, xindongnin A, and xindongnin B were isolated from the herb Isodon rubescens. These compounds were found to be potent inhibitors of NF-B transcription activity and the expression of its downstream targets, cyclooxygenase-2 and inducible nitric-oxide synthase. The mechanisms of action of the diterpenoids against NF-B are similar, but significant differences were also identified. All of the diterpenoids directly interfere with the DNA-binding activity of NF-B to its response DNA sequence. Oridonin and ponicidin have an additional impact on the translocation of NF-B from the cytoplasm to nuclei without affecting IB- phosphorylation and degradation. The effect of these compounds on the interaction of NF-B with consensus DNA sequences is unique. Different inhibitory effects were observed when NF-B bound to various DNA sequences. Both p65/p65 and p50/p50 homodimers, as well as p65/p50 heterodimer association with their responsive DNA, were inhibited. Kinetic studies on NF-B-DNA interaction indicate that the diterpenoids decrease the B_{max app} but have no effect on K_{d app}. This suggests that this class of compounds interacts with both p65 and p50 subunits at a site other than the DNA binding site and subsequently modulates the binding affinity of the transcription factor toward DNA with different NF-B binding sequences. The diterpenoid structure could therefore serve as a scaffold for the development of more potent and selective NF-B inhibitors that target regulated gene transcription.

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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