AACR: Chinese Herb and Modulation of NF-kB

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AACR Abstract Number: 3043

Exploration of a Chinese herb, isodon rubescens, for cancer treatment

with focus on modulation of nuclear factor-kappa B activity

Chung H. Leung, Her S. Shiah, Shwu H. Liu, Zaoli Jiang, Wenli Gao,

Wing Lam, P. Grill, Quan B. Han, Han D. Sun, Yung C. Cheng.

Yale University School of Medicine, New Haven, CT, PhytoCeutica Inc.,

New Haven, CT, State Key Laboratory of Phytochemistry and Plant

Resources in West China, Kunming Institute of Botany, Chinese Academy

of Sciences, Kunming, China.

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-êB 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-êB activity.

Their potencies against NF-êB 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-êB

transcriptional activity. The mechanism of action against NF-êB is

not due to blocking the nuclear translocation of NF-êB. On the other

hand, the interaction of the NF-êB 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-êB transcription. Its component diterpenoids as a whole

could be the active compounds responsible for this activity. The

mechanism against NF-êB could be due to the inhibition of interaction

of the NF-êB 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).

Presenter: Chung H. Leung

Affiliation: Yale University School of Medicine, New Haven, CT; E-

mail: duncanl@...

Copyright © 2004 American Association for Cancer Research. All rights

reserved. Citation information: Proceedings of the AACR, Volume 45,

March 2004.