Identification of a Potent Chemoprotective Agent for Aflatoxin-Induced Liver Cancer

John D. Groopman, Ph.D. and Thomas W. Kensler, Ph.D.
Johns Hopkins University Bloomberg School of Public Health
P01ES06052

Background: Aflatoxin is a carcinogenic compound produced by the mold Aspergillus flavus that contaminates some food products such as peanuts and corn. Aflatoxin exposure, which causes liver cancer, is widespread in China and is a major public health problem. Previous epidemiologic research by these NIEHS­supported investigators has shown that regular exposure to aflatoxin increases the risk for developing liver cancer about 3½-fold. However, persons infected with Hepatitis B virus and exposed to aflatoxin have about 60 times the risk of unexposed people.

Along with identifying the widespread problem, these investigators have conducted clinical trials which have established ”Proof of Principle” outcomes for chemopreventive approaches. To date these approaches have included molecular complexing with chlorophyllin to block the bioavailability of aflatoxin and induction of phase 2 genes, such as glutathione S-transferases (GSTs), with oltipraz to enhance metabolic detoxification and elimination of aflatoxins. Their current research reports a new breakthrough in treatment approaches to inhibit aflatoxin-induced liver cancer in laboratory rats.

Advance: Experiments with a compound known as CDDO-Im, have shown it to be highly effective in inhibiting the formation of precancerous lesions in the livers of rats exposed to aflatoxin. CDDO-Im belongs to a class of compounds known as triterpenoids, which are derived from acacia trees. Specifically at a dose of 1 micromole/kilogram body weight, CDDO-Im reduces the lesions by 85%; at 100 micromole/kilogram the lesions are reduced by greater than 99%. CDDO-Im also reduces levels of aflatoxin-DNA adducts by 40% to 90% over the range of doses. Microarray analyses confirm that many phase 2 and antioxidant genes are induced by CDDO-Im. Thus, relatively low doses of CDDO-Im induced protective genes, inhibit DNA adduct formation, and effectively block liver tumorigenesis.

Implications: According to the authors, ”The striking protection achieved in this model indicates that triterpenoids warrant further examination as chemopreventive agents against hepatocarcinogenesis in humans.” The potent CDDO-Im and/or other related compounds in the triterpenoid family could be effective agents to fight cancers with strong links to inflammation such colon or prostrate cancer.

Citation: Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, Sutter TR, Baumgartner KJ, Roebuck BD, Liby KT, Yore MM, Honda T, Gribble GW, Sporn MB, Kensler TW. 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. Cancer Res. 2006 Feb 15;66(4):2488-94.