Received for publication March 11, 2005.
Revised April 28, 2005.
Accepted for publication May 3, 2005.

NOVEL MECHANISM OF INHIBITION OF NF-B DNA- BINDING ACTIVITY BY DITERPENOIDS ISOLATED FROM ISODON RUBESCENS

Abstract

The development of specific inhibitors that can block 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 an herb, Isodon rubescens. These compounds were found to be potent inhibitors of NF-B transcription activity as well as the expression of its downstream targets, COX-2 and iNOS. The mechanisms of action of the diterpenoids against NF-B are similar but significant differences were also identified. All 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 interact with both p65 and p50 subunits at a site other than the DNA-binding site and subsequently modulate the binding affinity of the transcription factor towards 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.

Key words: Nitric oxide synthases, Tumor necrosis factor, NFkappaB, Fluorescence techniques, Regulation of gene expression, Cyclooxygenases, Transcription targets

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