Berkeley, California
December 3, 2008
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
University of California,
Berkeley, study appearing this week in the online early
edition of the journal Proceedings of the National Academy of
Sciences.
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.
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Indole-3-carbinol, or I3C, is a chemical compound found
in broccoli and other cruciferous vegetables and which
is known to stop the growth of breast cancer cells. UC
Berkeley researchers' discovery of how I3C works will
help them modify the compound to improve its anti-cancer
effects.
(Firestone & Bjeldanes labs/UC Berkeley) |
The new findings are the first to
explain how indole-3-carbinol (I3C) stops cell growth, and thus
provides the basis for designing 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."
"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.
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"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."
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.
By Robert Sanders |
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