A new study reports exciting findings about a compound that may have significant potential as a chemopreventive agent for a number of different cancers. The compound, CDDO-Imidazolide (Im), prevented the development of precancerous lesions in the livers of rats exposed to aflatoxin, a naturally occurring toxin that can cause liver cancer in humans. The study was published in the February 15 Cancer Research.

The compound was extremely effective, even at very low doses, says the study's senior author, Dr. Thomas Kensler, a cancer biologist at the Johns Hopkins Bloomberg School of Public Health. The results, he continues, are the first proof of principle that triterpenoids, the class of compounds to which CDDO-Im belongs, work as chemopreventive agents and do so by activating a signaling pathway regulated by the transcription factor Nrf2.

In previously published studies, a group at Dartmouth Medical School led by Drs. Michael Sporn and Karen Liby, together with Hopkins scientists, showed that triterpenoids activated Nrf2 in cell culture. This transcription factor regulates the activity of a number of so-called phase 2 genes; these genes help protect the body from toxins by producing enzymes that disarm toxic molecules.

"What excited us about this new study," Dr. Kensler says, "is that it demonstrates that CDDO-Im targets Nrf2 in vivo, and this leads to a very powerful induction of a defense or cell-survival mechanism that makes these animals very highly resistant to challenges by carcinogens."

To conduct the study, which was partly funded by NCI, the research team, led by Dr. Melinda Yates, used a rat model developed at Hopkins that has been extensively used to investigate other compounds as chemopreventive agents against aflatoxin-induced liver cancer.

Compared with the animals that did not receive CDDO-Im, those treated with the lowest dose had an 85-percent reduction in precancerous lesions in the liver; at the highest dose, there was a greater than 99-percent reduction. Other tests showed that the expression of several important antioxidant and anti-inflammatory genes regulated by Nrf2 was elevated after a single CDDO-Im dose. Additional tests in mice that did or did not express Nrf2 confirmed that CDDO-Im functions via this signaling pathway.

Two other compounds, DT3 and oltipraz, have had strong results in the same rat model, explains Dr. James Crowell, chief of the Chemopreventive Agent Development Research Group at NCI. One of the most important findings in this new study, he says, is that, at the lowest doses, CDDO-Im was 30-fold and 100-fold more potent than either of those drugs, respectively.

As with these other compounds, CDDO-Im stimulates an antioxidant response, Dr. Crowell adds, which helps to eliminate a specific carcinogen. "This could apply to other environmental chemicals that have carcinogenic potential," he says.

With support from the NCI RAID program, Dr. Sporn, an NCI Eminent Scholar, and colleagues at Dartmouth, including Drs. Tadashi Honda and Gordon Gribble, who synthesized CDDO-Im and related compounds, have spent the last decade developing triterpenoids for chemoprevention and treatment.

"CDDO-Im is exceptionally potent," Dr. Sporn says. "Our cell culture screens predicted that."

A small company in Dallas, Reata Pharmaceuticals, is leading the clinical development of several CDDO compounds, one of which is being tested in a phase I trial at the University of Texas M.D. Anderson Cancer Center to treat leukemia.

In animal models, CDDO-Im is especially potent at inducing protective enzymes in the liver and intestine, Dr. Sporn says, which, in addition to liver cancer, suggests it might have some applications in inflammatory bowel disease, hepatitis, and the prevention of liver metastases from colon cancer, one of the leading causes of colon cancer death.

By Carmen Phillips