NF-κB plays a central role in regulating genes responsible for tumor cell behaviors, immunological response and inflammatory process. Development of specific inhibitors, that can block NF-κB activation, is an approach for the treatment of cancer, autoimmune and inflammatory diseases. Isodon rubescens is an herb that is commonly used in China for the treatment of patients with certain types of cancer and also for a range of inflammatory related diseases. Several diterpenoids, oridonin, ponicidin, xindongnin A and xindongnin B, were isolated from this plant. These compounds are found to be potent inhibitors of NF-κB transcription activity as well as the expression of its downstream targets, COX-2 and iNOS. This inhibitory activity could partly explain the use of this herb in Chinese medicine. The mechanisms of action of the diterpenoids against NF-κB are similar but have some differences. All the diterpenoids directly interfere with the DNA-binding activity of NF-κB to its response DNA sequence. Oridonin and ponicidin have an additional impact on the translocation of NF-κB from cytoplasm to nuclei without affecting IκB-α phosphorylation and degradation. The action of these compounds on the interaction of NF-κB with DNA sequences is unique. Different inhibitory effects on NF-κB binding to various DNA sequences were observed. Both p65:p65 and p50:p50 homodimers, as well as p65:p50 heterodimer association with their responsive DNA could be inhibited. Kinetic studies on NF-κB-DNA interaction indicate that the diterpenoids decrease the Bmax app but have no effect on Kd 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-κB binding sequences. Diterpenoids could therefore serve as a scaffold structure for the development of more potent and selective NF-κB inhibitors that target on its regulated gene transcription. (Yung-Chi Cheng is a Fellow of the National Foundation for Cancer Research.)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]