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[Cancer Research 66, 2488-2494, February 15, 2006]
© 2006 American Association for Cancer Research

Epidemiology and Prevention

Potent Protection against Aflatoxin-Induced Tumorigenesis through Induction of Nrf2-Regulated Pathways by the Triterpenoid 1-[2-Cyano-3-,12-Dioxooleana-1,9(11)-Dien-28-Oyl]Imidazole

Melinda S. Yates1, Mi-Kyoung Kwak1, Patricia A. Egner1, John D. Groopman1, Sridevi Bodreddigari2, Thomas R. Sutter2, Karen J. Baumgartner3, B.D. Roebuck3, Karen T. Liby3, Mark M. Yore3, Tadashi Honda4, Gordon W. Gribble4, Michael B. Sporn3 and Thomas W. Kensler1

1 Johns Hopkins University, Baltimore, Maryland; 2 University of Memphis, Memphis, Tennessee; and 3 Dartmouth Medical School and 4 Dartmouth College, Hanover, New Hampshire

Requests for reprints: Thomas W. Kensler, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Room E7541, 615 North Wolfe Street, Baltimore, MD 21205. Phone: 410-955-4712; Fax: 410-955-0116; E-mail: tkensler{at}jhsph.edu.

Synthetic triterpenoid analogues of oleanolic acid are potent inducers of the phase 2 response as well as inhibitors of inflammation. We show that the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), is a highly potent chemopreventive agent that inhibits aflatoxin-induced tumorigenesis in rat liver. The chemopreventive potency of CDDO-Im was evaluated by measuring inhibition of formation of putative preneoplastic lesions (glutathione S-transferase P positive foci) in the liver of rats exposed to aflatoxin B1. CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 µmol/kg body weight and a >99% reduction at 100 µmol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by ~40% to 90% over the range of 1 to 100 µmol/kg body weight. Additionally, changes in mRNA levels of genes involved in aflatoxin metabolism were measured in rat liver following a single dose of CDDO-Im. GSTA2, GSTA5, AFAR, and EPHX1 transcripts are elevated 6 hours following a 1 µmol/kg body weight dose of CDDO-Im. Microarray analysis using wild-type and Nrf2 knockout mice confirms that many phase 2 and antioxidant genes are induced in an Nrf2-dependent manner in mouse liver following treatment with CDDO-Im. Thus, low-micromole doses of CDDO-Im induce cytoprotective genes, inhibit DNA adduct formation, and dramatically block hepatic tumorigenesis. As a point of reference, oltipraz, an established modulator of aflatoxin metabolism in humans, is 100-fold weaker than CDDO-Im in this rat antitumorigenesis model. The unparalleled potency of CDDO-Im in vivo highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids. (Cancer Res 2006; 66(4): 2488-94)




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2006 by the American Association for Cancer Research.