New compound may protect against liver cancer

Researchers have identified a new compound called CDDO-Im that protects against the development of liver cancer in laboratory animals. The compound appears to stimulate the enzymes that remove toxic substances from the cells, thereby increasing the cells' resistance to cancer-causing toxins. The National Institute of Environmental Health Sciences and the National Cancer Institute, agencies of the federal National Institutes of Health, provided funding to researchers at the Johns Hopkins Bloomberg School of Public Health for the two-year study.

The compound's effectiveness at very low doses suggests it may have similar cancer-fighting properties in humans. Researchers believe it may be particularly effective in preventing cancers with a strong inflammatory component, such as liver, colon, prostate and gastric cancers. The compound could eventually play a preventive role in a wide range of other illnesses such as neurodegenerative disease, asthma and emphysema.

The study results are featured on the cover of the February 15, 2006 issue of the journal Cancer Research.

"The results show that the potency of this compound is more than 100 times as great as that of other chemopreventive agents in protecting against cancer," said NIEHS Director David A. Schwartz, M.D. "This protective effect, combined with the compound's anti-inflammatory properties, make it an exciting avenue for the prevention of other diseases as well."

CDDO-Im belongs to a class of cancer-fighting compounds called triterpenoids. It is a synthetic compound derived from oleanolic acid, a naturally occurring substance found in plants all over the world. Research with other oleanolic derivatives showed marked anti-tumor activity in both animals and humans.

To test the effectiveness of CDDO-Im, researchers treated laboratory rats with either 0.1, 0.3, 1.0, 3.0 or 10 micromole doses of the compound. Two days after treatment with CDDO-Im, the rats were treated with aflatoxin, a naturally occurring toxin that causes liver cancer in animals.

Evaluation of the rat livers showed that the lowest concentration of CDDO-Im led to an 85 percent reduction in pre-cancerous lesions, abnormal growths that have a greater likelihood of developing into actual cancers. "This compound has a much greater effect at a far lower dose than any other compound currently used for preventing aflatoxin-induced cancer in humans," said Thomas Kensler, Ph.D., a cancer biologist with the Johns Hopkins Bloomberg School of Public Health and lead author on the study.

According to Kensler, CDDO-Im activates a protein called Nrf2 that plays a central role in protecting the cells against the toxic effects of environmental agents. "Nrf2 directs certain genes to stimulate the cell's defense mechanisms," he said. "The protein also stimulates key enzymes that can detoxify harmful agents like aflatoxin and remove them from the cell."

Like other compounds derived from oleanolic acid, CDDO-Im also has strong anti-inflammatory properties that make it ideally suited to the prevention of certain cancers. "When cells become inflamed, they can produce reactive molecules called free radicals that can damage DNA and promote cancer development," said Kensler. "CDDO-Im can also inhibit cancer formation by interfering with this inflammatory process."

Because it can stimulate the body's cancer-fighting capabilities at such low doses, Kensler believes that CDDO-Im is an excellent candidate for cancer prevention use in humans. "If this compound can produce such a potent and dramatic reduction in the number of pre-cancerous growths, it should have an equally dramatic impact on the development of actual cancers," he said.

In addition to serving as a valuable tool in the development of new cancer prevention interventions, CDDO-Im may offer protection in a wide range of other disease settings. "We know that the Nrf2 protein plays a role in regulating many different kinds of genes involved in protecting the cell from harmful agents," said Kensler. "It follows that activation of the Nrf2 pathway with CDDO-Im could provide protection against a number of diseases where environmental agents play important roles in their causes."

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NIEHS, a component of the National Institutes of Health, supports research to understand the effects of the environment on human health. For more information on cancer prevention and other environmental health topics, please visit the NIEHS website at http://www.niehs.nih.gov/home.htm.

Note: Triterpenoid compounds are currently under development by Dr. Michael Sporn and colleagues at Dartmouth Medical School.

Reference: M. Yates, M. Kwak, P. Egner, J. Groopman, S. Bodreddigari, T. Sutter, K. Baumgartner, B. Roebuck, K. Liby, M. Yore, T. Honda, G. Gribble, M. Sporn and T. Kensler. 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 Research 66(4), February 2006.


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