Broccoli compound targets key enzyme in late-stage cancers

An anti-cancer compound in broccoli and cabbage, indole-3-carbinol, is undergoing clinical trials in men with prostate cancer and women with breast cancer because it was found to stop the growth of these cancers in mice.

Now scientists have discovered more about how it works. They've found that in breast cancer it lowers the activity of an enzyme associated with rapidly advancing cancer growth, according to a University of California, Berkeley, study appearing this week in the online early edition of Proceedings of the National Academy of Sciences.

The new findings are claimed as the first to explain how indole-3-carbinol (I3C) stops cell growth. This new understanding is expected to speed designs for improved versions of the chemical that would be more effective as a drug and could work against a broader range of breast as well as prostate tumors.

"I think one of the real uses of this compound and its derivatives is combining it with other kinds of therapies, such as tamoxifen for breast cancer and anti-androgens for prostate cancer," said coauthor Gary Firestone, UC Berkeley professor of molecular and cell biology. "Humans have co-evolved with cruciferous vegetables like broccoli and Brussels sprouts, so this natural source has a lot fewer side effects."

Broccoli"This is a major breakthrough in trying to understand what the specific targets of these natural products are," said coauthor Leonard Bjeldanes, UC Berkeley professor of toxicology. "The field is awash with different results in various cells, but no real identification of a specific molecular target for these substances. The beauty of identifying the target like this is that it suggests further studies that could augment the activity of this type of molecule and really specify uses for specific cancers."

Firestone, Bjeldanes and their colleagues showed that I3C inhibits the enzyme elastase, which at high levels in breast cancer cells heralds a poor prognosis: decreased response to chemotherapy, reduced response to endocrine treatment and reduced survival rates.

Elastase is an enzyme that shortens a cellular chemical, cyclin E, that is involved in controlling the cell cycle. The shortened version of cyclin E accelerates the cell cycle, making cancer cells proliferate faster. Firestone showed that I3C prevents the elastase shortening of cyclin E, thereby arresting development of breast cancer cells.

For more than 15 years, Firestone, Bjeldanes and their colleagues have studied the anti-cancer benefits of vegetables in the cabbage family that are lumped together in the genus Brassica and, because of their cross-shaped flowers, are often referred to as cruciferous vegetables.

Though the anti-cancer benefits have been recognized since the 1970s, the mechanism is only now being discovered, in part through the work of Firestone, Bjeldanes and their UC Berkeley colleagues. "We have connected the dots on one extremely important pathway" by which indole-3-carbinol works, Firestone said.

In previous work, they found that indole-3-carbinol interferes with more than cell proliferation. It also disrupts the migration and alters adhesion properties of cancer cells, as well as counteracts the survival ability of cancer cells, all of which are implicated in cancer cell growth. To have such broad downstream effects, I3C must act at the beginning of a major cellular pathway, Firestone said. The newly reported research pins this activity to elastase and its effect on cyclin E.

Bjeldanes noted that I3C is available as a supplement and is a preferred preventative treatment for recurrent respiratory papillomatosis, a condition involving non-malignant tumors of the larynx. Improved versions of the chemical could thus help treat cancers other than those of the breast and prostate.

Graduate student Ida Aronchik and recent Ph.D. recipient Hanh H. Nguyen, along with colleagues in the Firestone and Bjeldanes labs, have already chemically modified I3C and boosted its activity in cell culture by at least a factor of 100. The lab teams currently are probing the elastase structure and how I3C interacts with it to identify the best parts of the I3C molecule to modify.

I3C is only one of many plant-derived chemicals, called phytochemicals, that Firestone is investigating in his laboratory as potential anti-cancer agents. Among them is the anti-malarial drug artemisinin. Last month, the Journal of Biological Chemistry accepted a paper by Firestone and his colleagues showing that artemisinin blocks prostate cancer cell growth by interfering with the same intracellular pathway as does I3C. This pathway involves the transcription factor SP1, which latches onto other genes to boost their activity.

"SP1 could be a generalized target of phytochemicals," Firestone said. "Phytochemicals work because they interact with and inhibit enzymes that control a host of cellular processes, including migration and adhesion."

Roderick Dashwood, a cancer researcher at Linus Pauling Institute who has published positive evidence on the effect of broccoli-derived Sulforaphane (SFN) on prostate cancer in mice and men, offers cautious view in Pharmacol Res. March 2007. High intake of cruciferous vegetables, Dashwood writes, "has been associated with lower risk of lung and colorectal cancer in some epidemiological studies." And compounds from the broccoli family of vegetables "alter the metabolism or activity of sex hormones in ways that could inhibit the development of hormone-sensitive cancers," he says. But evidence that cruciferous vegetable intake reduces breast or prostate cancer in humans "is limited and inconsistent."

Organizations such as the National Cancer Institute recommend the consumption of five to nine servings of fruits and vegetables daily, but separate recommendations for cruciferous vegetables have not been established. Dashwood notes that broccoli-derived chemicals such as sulforaphane and indole-3-carbinol (I3C) "have been implicated in a variety of anticarcinogenic mechanisms, but deleterious effects also have been reported in some experimental protocols, including tumor promotion over prolonged periods of exposure." Eating cruciferous vegetables "may decrease cancer risk, but the protective effects may be influenced by individual genetic variation (polymorphisms)" in the individual.

The research is supported by the National Cancer Institute. Other coauthors of the paper are Gloria A. Brar, currently a graduate student at the Massachusetts Institute of Technology, and former UC Berkeley undergraduate David H. H. Nguyen, now a graduate student at New York University.

Gary Firestone and Len Bjeldanes are on the Scientific Advisory Board of BIONOVO, INC., registered with the SEC as "a clinical stage drug discovery and development company focusing on women’s health and cancer, two large markets with significant unmet needs. Building on our understanding of the biology of menopause and cancer, we design new drugs derived from botanical sources which have novel mechanisms of action. Based on the results of our clinical trials and preclinical studies to date, we believe that we have discovered new classes of drug candidates with the potential to be leaders in their markets." Firestone and Bjeldanes are also cofounders of Berkeley BioSciences, Inc., which has licensed the University's patent applications on the broccoli compound DIM and is researching and developing immune-enhancing nutritional supplements and therapeutics based on this discovery.


INDOLE-3 CARBINOL Linus Pauling Institute

Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats . . . and consequent modulation of estrogen metabolism "In the present study using rat uterine cancer model, dietary treatment with I3C clearly demonstrated promoting effects on endometrial adenocarcinoma development. I3C can act both as an inhibitor and promoter of carcinogenesis, and our data are in line with the promoting results observed earlier with several animal carcinogenesis models. As for a cause of the complex effects, I3C is unstable under the acid condition and a number of acid-catalyzed metabolites such as 3,3'-diindolylmethane and indolcarbazole are produced in the gut. . . . "

A Phase I Study of Indole-3-Carbinol in Women: Tolerability and Effects(2005) Completed.
Vanderbilt University Institute for Cancer Prevention No Results posted

Single-Dose and Multiple-Dose Administration of Indole-3-Carbinol to Women: Pharmacokinetics Based on 3,3'-Diindolylmethane (2006)

A Potent Indole-3-Carbinol–Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells (2007)

Clinical Trials:

Effects of Brassica or Indole-3-Carbinol on Prostatectomy Patients With PSA Recurrence
This study has been completed.

Brassica Vegetables or Indole-3-Carbinol in Treating Patients With PSA Recurrence After Surgery for Prostate Cancer
Vanderbilt. This study is ongoing, but not recruiting participants.

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