Chalk Up Another One For Broccoli! Chemical In Vegetable Shown To Halt Growth Of Breast Cancer Cells

Researchers at the University of California at Berkeley have shown that the chemical indole-3-carbinol, a component of broccoli and other members of the Brassica genus, halts the growth of breast cancer cells, an attribute that may make it a good cancer therapy in combination with other drugs.

Indole-3-carbinol works by halting the cell cycle in breast cancer cells without actually killing the cells, the scientists found. The cell cycle is a rigidly prescribed series of steps a cell must go through before it can divide in two, involving the duplication of the cell's contents and a final split.

"If you can alter specific components of the cell cycle, you can stop the growth of cancer cells without killing normal cells," says Gary Firestone, coauthor of a report in the Feb. 13 issue of the Journal of Biological Chemistry. "Many people are trying to find drugs that manipulate the cell cycle in hopes of discovering effective anti-tumor agents with reduced side effects."

Firestone is a professor in the Department of Molecular and Cell Biology and a molecular endocrinologist in the Cancer Research Laboratory at UC Berkeley.Significantly, the chemical indole-3-carbinol interferes with the cell cycle in a way that hints at a totally new signaling pathway in the cell, Firestone says.

"The chemical seems to be working by a very unusual mechanism," he says. "It turns off a gene for an enzyme important in the cell's growth cycle, pointing to a possible target for other drugs."

The compound also works independently of the hormone estrogen, which makes it a good candidate for use in combination therapy with drugs that interfere with estrogen, such as the potent breast cancer drug tamoxifen.The UC Berkeley scientists treated breast cancer cells in culture with indole-3-carbinol and tamoxifen together and found an even stronger inhibition of growth.

"It looks like these two work synergistically -- they're better together than either alone," Firestone says.

"Indole-3-carbinol hits the cancer from a different angle than other anticancer drugs, which makes it a very powerful and interesting chemical," adds coauthor Leonard F. Bjeldanes, professor of toxicology in the College of Natural Resources at UC Berkeley.

"These vegetables are not only great to eat -- there might also be a therapeutic find on your dinner plate," concludes Carolyn M. Cover, an endocrinology graduate student working in Firestone's laboratory and first author on the paper. Three undergraduate students in the Department of Molecular and Cell Biology also are coauthors on the paper: Jean Hsieh, Susan H. Tran and Gloria S. Kim.

Eating vegetables is good for you because, among other things, they lower the risk of cancer, as shown by numerous epidemiologic studies. In particular, high vegetable diets have been linked to a lowered risk of breast cancer, presumably because some of the chemicals in vegetables suppress the hormone estrogen, which stimulates the growth of breast cells and breast cancer cells alike.

One of the chemicals directly implicated is indole-3-carbinol, a component of vegetables in the Brassica group -- a genus that includes broccoli, cabbage, Brussels sprouts, bok choy, kale, chard and turnips. Bjeldanes has studied the properties of indole-3-carbinol for more than 15 years, most recently its anti-estrogenic effects.

"What's exciting about this is that indole-3-carbinol has low toxicity but is a very effective agent against mammary tumors -- it's one of the most effective agents at blocking tumorigenesis in rats," Bjeldanes says. "Given in the diet, indole-3-carbinol can block 95 percent of all mammary tumors in rats."

More than two years ago Bjeldanes teamed up with Firestone to study the specific effects of indole-3-carbinol on breast cancer cells. One of the uncertainties was what specifically was responsible for the anti-estrogen effects of indole-3-carbinol: the chemical itself; or one of the compounds it is converted to when it hits the acids in our stomach, or when it reacts with other chemicals in the cell.In their new study, Firestone, Bjeldanes and their student colleagues showed that indole-3-carbinol does not act on estrogen at all, but rather works through a different mechanism to halt the cell cycle. Evidently, Bjeldanes says, the chemicals produced when indole-3-carbinol reacts with stomach acid are the ones responsible for the anti-estrogen and certain toxic effects of the broccoli compounds.

Indole-3-carbinol specifically causes a sudden drop in the production of the enzyme CDK6, or cyclin-dependent kinase 6. CDK6 is one of several protein complexes targeted by hormones that regulate the progression of the cell cycle, and was identified only three years ago.

The effect of indole-3-carbinol on CDK6 will draw more attention to that protein and its role in the cell, which is still poorly understood, Bjeldanes says.

"With the discovery of indole-3-carbinol's effect on CDK6, that protein now becomes the focus for development of drugs that block that pathway," he says.

The effect on CDK6 also is important because this complex has been found in elevated levels in several types of tumors, including brain tumors called gliomas. Firestone suggests that the chemical might be most effective in those tumors that exhibit high levels of CDK6.

"The problem with breast cancer is that it is many types of cancers, in many different cell types and showing activation of many different oncogenes," he says. "The more drugs you have available to throw at the cancer, and the more pathways these drugs target, the better."

Because indole-3-carbinol is changed as it is processed through the digestive system, it would have to be delivered directly to the tumor, perhaps by injection into the bloodstream, or chemically altered to survive the strong enzymes and acids in the stomach, Bjeldanes says.

Firestone and Bjeldanes are continuing their collaboration to look at the effects of indole-3-carbinol on other types of cancer cells, and plan to test its effects on human tumors growing in a special strain of mice. Firestone also hopes to learn how indole-3-carbinol regulates CDK6, specifically whether it acts through a previously unknown receptor for indoles.

In his own lab, Bjeldanes is studying the anti-estrogenic modes of action of indole products, and is looking for other chemicals in the Brassicas and other vegetable groups that might have antitumor activity.

"The Brassicas are seemingly mundane foods that most people can get hold of readily, yet we find that one of the chemicals in them affects an important and essential part of the cell cycle," Bjeldanes says. "This work emphasizes the importance of non-nutrients in foods, and we're now screening other vegetables and plants in hopes of finding more useful phytochemicals."

The work was supported by the Department of Defense Army Breast Cancer Research Program and the University of California Breast Cancer Research Program.