John Hopkins University
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.
 T
his shows the differences in the stomach lining of normal mice
given the benzpyrene carcinogen–they have some natural protection–and
the knockout mice where the protective system has been destroyed.
The large mass in the knockouts, which looks like mashed potato,
is tumor.
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.
|
