There is still no effective treatment for either cancer of the liver or pancreas. New approaches in chemotherapy need to be explored. In designing a strategy for developing drugs against these tumors, inhibition of the NF-κB pathway was suggested. Isodon rubescens is commonly used in China for the treatment of patients with these types of cancer and also for a range of inflammatory diseases. However, the underlying mechanisms are not clear. Our study indicated I. rubescens extracts and structurally similar diterpenoids could suppress growth of human hepatocellular carcinoma cells, HepG2 and pancreatic ductal carcinoma cells, PANC-1, in cell culture. Cells with overexpression of P-gp170(MDR-1) or MRP and cells resistant to camptothecin or VP-16 do not show cross resistance to this class of compounds. In addition, I. rubescens extracts, as well as its diterpenoid components were found to be potent inhibitors against NF-κB activity. Their potencies against NF-κB appear to correlate with those against tumor cell growth. The inhibition of cell growth may therefore be associated with the ability of those diterpenoids to inhibit NF-κB transcriptional activity. The mechanism of action against NF-κB is not due to blocking the nuclear translocation of NF-κB. On the other hand, the interaction of the NF-κB complex to its response DNA sequence could be inhibited in vitro and was found to be redox sensitive. This reaction could be compromised by dithiothreitol, glutathione or thioredoxin. HPLC/MS analysis revealed that naturally occurring reducing agents including glutathione could form conjugates with those redox sensitive diterpenoids. This study therefore suggested that the mechanism of action of I. rubescens as an anti-cancer or anti-inflammatory herb could be partly due to its activity against NF-κB transcription. Its component diterpenoids as a whole could be the active compounds responsible for this activity. The mechanism against NF-κB could be due to the inhibition of interaction of the NF-κB active complex with its target DNA sequence. Its potential for treatment of cancer of the liver and pancreas should be further explored (This work was supported, in part, by the National Foundation for Cancer Research).

[Proc Amer Assoc Cancer Res, Volume 45, 2004]