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.

Abstract

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 micromol/kg body weight and a >99% reduction at 100 micromol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by approximately 40% to 90% over the range of 1 to 100 micromol/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 micromol/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.

• Authors: Melinda S Yates, Mi-Kyoung Kwak, Patricia A Egner, John D Groopman, Sridevi Bodreddigari, Thomas R Sutter, Karen J Baumgartner, B D Roebuck, Karen T Liby, Mark M Yore, Tadashi Honda, Gordon W Gribble, Michael B Sporn, Thomas W Kensler
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 4 Pg. 2488-94 (Feb 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16489057 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Anticarcinogenic Agents
• DNA Adducts
• Imidazoles
• NF-E2-Related Factor 2
• aflatoxin B1-DNA adduct
• Oleanolic Acid
• Aflatoxin B1

Topics

• Aflatoxin B1 (metabolism, pharmacokinetics, toxicity)
• Animals
• Anticarcinogenic Agents (pharmacology)
• DNA Adducts (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Imidazoles (pharmacology)
• Inactivation, Metabolic
• Liver (metabolism)
• Liver Neoplasms, Experimental (chemically induced, metabolism, prevention & control)
• Male
• NF-E2-Related Factor 2 (biosynthesis, metabolism)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Rats
• Rats, Inbred F344