| Studies Show Powerful
Natural Anti-Cancer System Exists
Scientists
at Johns Hopkins and Tsukuba University in Japan have confirmed the existence
of a long-suspected natural system the body uses to block the cancer-causing
effects of toxic chemicals in food and the environment.
The system
hinges on a sharp boost in protective enzymes, called phase II enzymes,
which can dispose of toxic chemicals. The enzymes effectively neutralize
toxins’ ability to damage DNA and trigger cancer, the researchers say.
In two studies
appearing in the current Proceedings of the National Academy of Sciences,
they’ve not only demonstrated the fundamental workings of the system, but
have also pinpointed the key "switch" that regulates it. "We’ve gained
long-awaited proof of a basic mechanism that can reduce the risk of cancer,"
says molecular pharmacologist and team member Paul Talalay, M.D.
Scientists
already know that natural substances in plants, such as the sulforaphane
in broccoli, as well as some man-made chemicals, can tap into this system
— that they’re somehow "chemoprotective" — but the route hasn’t been clear.
The new work, a result of 20 years’ research, "confirms that
raising the levels of phase II enzymes can offer a highly effective way
to achieve protection against carcinogenesis," says
Talalay. "We always had faith," he adds; "Now, in our animal studies, we
have a direct demonstration."
"Our precise
understanding of this system should make it fairly easy to design drugs
that can fine-tune it," says team leader Thomas W. Kensler, Ph.D., a Hopkins
toxicologist who’s now overseeing early clinical trials of one such drug
in China.
"We have evidence
that we can increase the system’s levels of protection in people," he says,
"and are planning long-term studies that would reveal any lowered incidence
of cancer."
In the study,
the researchers focused on strategies cells use to control activity of
the phase II enzymes. "The levels of these enzymes are tightly controlled
by the cellular equivalent of a dimmer switch," says Kensler. The scientists
knocked out the switch — a protein called Nrf2 — in genetically engineered
mice and saw the activity of phase II enzymes drop dramatically compared
with mice whose "switch gene" was intact.
When they exposed
both the knockout mice and normal mice to benzpyrene, a potent carcinogen
in cigarette smoke, both developed tumors, but the knockouts — apparently
disconnected from the protective system — had significantly more.
In a more telling
demo of the system, the scientists gave both the normal and the knockout
mice a drug called oltipraz along with the benzpyrene carcinogen. Oltipraz
has been used for parasite infections. But it was also shown in earlier
Hopkins studies to raise levels of phase II enzymes and lower cancer risk.
In the study,
carcinogen-exposed normal mice on oltipraz had their tumor number cut by
half. But the knockout mice were tumor-ridden, even with the protective
drug. "This shows the great importance of the Nrf2 ‘switch,’" says Tsukuba
University molecular biologist Masayuki Yamamoto, M.D., Ph.D.; "Without
it, the mice couldn’t be protected."
Earlier work
by Yamamoto showed that protective chemicals, such as those in plants,
work by sparking cells’ release of Nrf2. Then Nrf2 activates a common DNA
sequence on the genes of all phase II enzymes, switching them on.
"Scientists
have tried to learn what makes some people more susceptible to cancer,"
Kensler adds. "They’ve looked at genes for single phase II enzymes here
and there. But with NRf2, you have the control for all of them. With
slight changes in the ‘switch,’ you can get a tremendous step up in a body’s
sensitivity to cancer agents."
Turning the
system up or down might have value, says Yamamoto. "By turning down an
organism’s ability to squelch carcinogens, you could get an exquisitely
sensitive model for testing, say, which pollutants in the Chesapeake Bay
cause tumors to form. Likewise, you could turn it up and, in theory, increase
any animal’s resistance to cancer or, perhaps, other diseases."
The researchers
believe the system is a common, general one in many animals. "Also," says
Kensler, "we think it may be part of a broader way animals deal with many
types of toxicity — not just carcinogens. Toxicity plays a role in many
conditions such as atherosclerosis and neurodegenerative diseases."
The studies
were funded by grants from the National Institutes of Health and by gifts
from the Lewis and Dorothy Cullman Foundation, New York.
The Nrf2-depleted
mice were developed by Masayuki Yamamoto, M.D., Ph.D.
Others on the
research teams were Minerva Ramos-Gomez, Sc.M., Mi-Kyoung Kwak, Ph.D.,
Patrick M. Dolan, B.S. and Albena Dinkova-Kostova, Ph.D., from Hopkins;
and Ken Itoh, M.D., Ph.D., from Tsukuba University in Japan.
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