An anti-cancer compound found in broccoli and cabbage works by lowering the activity of an enzyme associated with rapidly advancing breast cancer, according to a UC Berkeley study.
The compound, indole-3-carbinol, is already undergoing clinical trials in humans because it was found to stop the growth of breast and prostate cancer cells in mice.
The study appears this week in the online early edition of the journal Proceedings of the National Academy of Sciences.
The new findings are the first to explain how I3C stops cell growth, and provides the basis for designing improved versions of the chemical.
They might be more effective as a drug and could work against a broader range of breast as well as prostate tumors, scientists said.
"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 Gary Firestone, one of the UC Berkeley biology professors who wrote the study. "Humans have co-evolved with cruciferous vegetables like broccoli and Brussels sprouts, so this natural source has a lot fewer side effects."
"This is a major breakthrough in trying to understand what the specific targets of these natural products are," said Cal toxicology professor Leonard Bjeldanes, who also helped write the study.
Firestone, Bjeldanes and their colleagues showed that I3C inhibits the enzyme elastase, which at high levels in breast cancer cells means a poor prognosis: decreased response to chemotherapy, reduced response to endocrine treatment and reduced survival rates.
How It Works...
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 I3C interferes with more than cell growth.
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.
Already Used as Supplement
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, researchers said.
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."
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.
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