Compound Linked to the Prevention of Liver Cancer

A new compound, CDDO-Im, has been shown to protect laboratory animals
against the development of liver cancer, according to results of the study
published in the February 15, 2006 issue of Cancer Research. The compound
appears to stimulate the enzymes that remove toxic substances from the cells
and increase the cells’ resistance to cancer-causing toxins. Researchers
reported that the compound may also have similar cancer-fighting effects in
humans and believe that CDDO-Im may be effective in preventing cancers with
a strong inflammatory component (eg, liver, colon, prostate, or gastric
cancers). The CDDO-Im compound was found to be 100 times as potent as other
chemo-preventative agents in protecting against cancer. The study team is
hopeful that the compound also has the potential to prevent other illnesses,
including neurodegenerative disease, asthma, and emphysema.

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http://cancerres.aacrjournals.org/cgi/content/abstract/66/4/2488

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

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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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