<http://www.sciam.com/print_version.c...-E7F2-99DF-3C8
4BB412D1D3B51>

Spice Healer

An ingredient in curry shows promise for treating Alzheimer's, cancer
and other diseases

Scientific American

Searching for new drugs by milling through ancient folk pharmacopoeia
or by just picking a plant while walking in the woods has a decidedly
checkered history. Many well-established therapeutic compounds
originated in trees, shrubs, mollusks, even dirt. Aspirin came from
willow bark, cholesterol-lowering statins from a mold, and the
antimalarial artemisinin from a shrub used in traditional Chinese
medicine. Yet after raising $90 million during the 1990s in a much
publicized bid to tap indigenous knowledge for new drug leads, Shaman
Pharmaceuticals had to lower its sights until it was doing nothing more
than selling its products as nutritional supplements before finally
shutting its doors for good a few years ago.

Now the trend may be reversing itself again. Recently a number of
natural compounds--such as resveratrol from red wine and omega-3 fatty
acids from fish oil--have begun to receive close scrutiny because
preliminary research suggests they might treat and prevent disease
inexpensively with few side effects. Turmeric, an orange-yellow powder
from an Asian plant, Curcuma longa, has joined this list. No longer is
it just an ingredient in vindaloos and tandooris that, since ancient
times, has flavored food and prevented spoilage.

A chapter in a forthcoming book, for instance, describes the
biologically active components of turmeric--curcumin and related
compounds called curcuminoids--as having antioxidant,
anti-inflammatory, antiviral, antibacterial and antifungal properties,
with potential activity against cancer, diabetes, arthritis,
Alzheimer's disease and other chronic maladies. And in 2005 nearly 300
scientific and technical papers referenced curcumin in the National
Library of Medicine's PubMed database, compared with about 100 just
five years earlier.

Scientists who sometimes jokingly label themselves curcuminologists are
drawn to the compound both because of its many possible valuable
effects in the body and its apparent low toxicity. They ponder how the
spice or its derivatives might be used, not just as a treatment but as
a low-cost preventive medication for some of the most feared ailments.
As a treatment, it also has some enticing attributes. Because curcumin
targets so many biological pathways, it could have benefits for cancer
therapy: malignant cells may be slow to acquire resistance to it and so
might have to go through multiple mutations to avoid the substance's
multipronged attack.

But is the compound ready for widespread use? Some work offers grounds
for caution. Among the more than 1,700 references to curcumin in PubMed
are studies showing how a compound that can affect so many biological
pathways can sometimes hit the wrong switch and actually help to foster
disease.

Long Medical History

Known as HALDI in HINDI, jiang huang in Chinese, manjal in Tamil (and
just plain "yuk" as the yellow stain on a white T-shirt from the
splatting of ballpark mustard), turmeric has a medicinal history that
dates back 5,000 years. At that time it was a key medicament for wound
healing, blood cleansing and stomach ailments in India's Ayurvedic
system of medicine.

The first record in PubMed of research on the biological activity of
curcumin dates back to 1970, when a group of Indian researchers
reported the effects of the compound on cholesterol levels in rats. The
pace of studies picked up in the 1990s; one of the leaders was Bharat
Aggarwal, a former scientist at Genentech who, before turning to
curcumin, had taken another approach to seeking cancer treatments. That
work led him circuitously to the compound.

In the 1980s Aggarwal and his team at Genentech were the first to
purify two important immune molecules--tumor necrosis factor (TNF)
alpha and beta--that have been identified as potential ?anticancer
compounds. These molecules can, in fact, kill cancer cells when
deployed in localized areas, but when circulated widely in the
bloodstream, they take on different properties, acting as potent tumor
promoters. The TNFs activate an important protein, nuclear factor kappa
B (NF kappa B), which can then turn on a host of genes involved in
inflammation and cell proliferation.

This link between inflammation and the unchecked proliferation of
cancer cells prompted Aggarwal to return to his roots. In 1989 he moved
to the University of Texas M. D. Anderson Cancer Center and began
looking for compounds that might quell inflammation and have an
anticancer effect. Remembering from his youth in India that turmeric
was an anti-inflammatory in the Ayurvedic literature, he decided to
give the spice a try. "We took some from the kitchen and threw it on
some cells," he remembers. "We couldn't believe it. It completely
blocked TNF and NF kappa B."

Can an ingredient in curry treat diseases from Alzheimer's to cancer?

Aggarwal has gone on to publish studies showing that blocking the NF
kappa B pathway with curcumin inhibits the replication and spread of
various types of cancer cells. This work has served as a jumping-off
point for early, small clinical trials at M. D. Anderson using curcumin
as an adjunct therapy to treat pancreatic cancer and multiple myeloma.
Trials are beginning or under way elsewhere for prevention of colon
cancer and Alzheimer's disease, among others. And early cell-based or
animal studies have shown that curcumin may act against a range of
inflammatory diseases, including pancreatitis, arthritis, inflammatory
bowel disease, colitis, gastritis, allergy and fever. It has also shown
some promise for diabetes and autoimmune and cardiovascular diseases.

So far the large clinical trials needed to prove efficacy against
cancer and other diseases have yet to be conducted. But Aggarwal has
nonetheless become an aggressive champion for a spice that Vasco da
Gama brought back to Europe from his voyages eastward. Aggarwal's
chapter in a new textbook that he co-edited is entitled "Curcumin: The
Indian Solid Gold."

M. D. Anderson, a world-leading cancer institution, has also begun to
promote the use of curcumin more than would be expected for a treatment
that has not gone through the rigors of full clinical trials. The
"frequently asked questions" section on its Web site recommends buying
curcumin from a specific wholesaler, for which Aggarwal has served as a
paid speaker. That company even issued a press release declaring that
its product is the "ingredient of choice" of M. D. Anderson.

The FAQ section suggests that cancer patients gradually work up to a
daily dose of eight grams a day, some 40 times the amount consumed in
the average Indian diet. Most pharmaceuticals, in contrast, are meted
out in milligrams. At one point, the Web site had even asserted: "By
the end of eight weeks, a significant improvement is expected." Asked
whether he was worried that any side effects might emerge at a dosage
of eight grams, Aggarwal said that small clinical trials at other
institutions have dosed up to 12 grams and that patients would have
notified him if any untoward effects had occurred with the dosage
recommended by M. D. Anderson. The researcher, who takes a curcumin
pill every day, shuns the caution typical of investigators before
well-controlled, large-scale clinical trials have been conducted.
"People take a lot of other supplements, and I don't think you need
anything else if you're taking this," Aggarwal says.

Does Curcumin Abet Cancer?

The m. d. anderson faqs and the stream of press releases from various
institutions on the wonders of curcumin ignore a small portion of the
literature that points to a dark side: the possibility that this spice
may sometimes actually encourage the survival of cancer cells. In 2004
Yosef Shaul in the department of molecular genetics at the Weizmann
Institute of ?Science in Rehovot, Israel, was studying an enzyme, NQO1,
that regulates the amount of a well-known protein called p53. When p53
levels increase in cells, the protein institutes a defensive maneuver
for the organism by inducing cancerous or damaged cells to stop
dividing or even to commit suicide.

Shaul and his colleagues had found that an anticoagulant, dicoumarol,
and related compounds blocked NQO1, which prevented p53 from doing its
job. The researchers wondered what would happen if they exposed p53 in
normal and myeloid leukemia cells to antioxidants such as curcumin and
resveratrol. To their surprise, curcumin, by inhibiting the same
enzyme, stopped p53 from sending aberrant cells to the gallows, a
finding that was reported in 2005 in the Proceedings of the National
Academy of Sciences USA. A few other researchers have published similar
results. Aggarwal responds to this body of work by pointing to studies
that show the opposite, that curcumin actually activates p53.

Clinical researchers will now have to address whether Shaul's work in
cell cultures relates to what happens when a person ingests the
compound. The curcumin concentrations used by the Weizmann team in cell
cultures--measuring 10 to 60 µM (micromolar)--are roughly comparable to
levels reached in some of the test-tube experiments conducted at M. D.
Anderson. But because curcumin is absorbed poorly from the gut into the
bloodstream and is also broken down in the body rapidly, a patient
consuming eight grams would probably end up with a concentration in
blood plasma no higher than about 2.0 µM, Shaul notes, although that
level could range higher in the gastrointestinal tract and in the
liver. It could also remain elevated if researchers develop various
means of increasing the concentration of curcumin in the bloodstream.

M. D. Anderson's FAQs might convey the impression of certitude by
prescribing an eight-gram dose. But the low presence of curcumin in the
blood--and the corresponding need to elevate the amount consumed if the
substance does indeed fight disease--is a challenge that will continue
to nag curcumin researchers. The animal studies that investigators cite
as suggestive of curcumin's diverse benefits have generally used less
than the equivalent of eight grams in humans, and blood concentrations
have usually been in the nanomolar range. "We don't know how to explain
how such low concentrations of curcumin can be beneficial in animals
tested," Shaul states.

Dose is everything for a new drug--any therapeutic agent, including
aspirin, turns toxic at high levels. For most new pharmaceuticals, the
best dose for achieving the desired blood plasma levels is usually
found through round after round of preclinical trials in cell cultures
and mice. Yet drug companies are not battling one another to be the
first to conduct these tests on curcumin. They have a preference for
highly targeted therapeutics: hitting a specific receptor, for
instance, may treat disease while lowering side effects, whereas a drug
with multiple actions could, in theory, increase the chance that an
unwanted effect will occur. Another reason is the nettlesome issue of
property rights for folk medicines.

Turmeric is a poster child for one of the most noted
intellectual-property cases on biopiracy, which pitted an Indian
government-supported research organization against a 1995 patent issued
to the University of Mississippi for the use of the spice for wound
healing. The U.S. Patent and Trademark Office invalidated the patent
after the Indian Council for Scientific and Industrial Research
questioned whether one criterion for patentability--that an invention
be new--had been met. The council objected by pointing to a 1953 Indian
journal article about the spice and by offering a citation about
turmeric's healing properties from an ancient Sanskrit text.

The patent office has subsequently issued patents for specific uses for
curcumin as an isolate. But the rejection means that drug companies
will never obtain a "product" patent with a much broader scope that
would help them to fend off competitors for drugs based on the spice. A
few small companies are still trying to exploit the substance's promise
by changing its chemical composition to enhance activity and, by
creating a novel compound, to bolster intellectual-property protection.

AndroScience in San Diego plans to enter the first phase of clinical
trials this year with a drug candidate for acne based on compounds
derived from curcumin that were discovered in collaboration with the
University of North Carolina at Chapel Hill. Similarly, Curry
Pharmaceuticals in Research Triangle Park, N.C., is trying to raise
financing to move curcumin derivatives from Emory University into
clinical trials. But in an age of targeted pharmaceuticals, venture
capitalists, leery of side effects, have been hesitant to back new
drugs that act on multiple pathways. For his part, Aggarwal, even
though he is a co-founder of Curry Pharmaceuticals and holds patents on
curcumin, asserts that chemists may have trouble improving on natu
modifying curcumin may only introduce unwanted side effects in
patients, he says.

If the multitude of developmental hurdles can be overcome and safety
can be assured, curcumin might provide an inexpensive alternative to
mainstream pharmaceuticals. Based on positive results in rodents, Greg
Cole of the University of California, Los Angeles, and the Veterans
Administration, is organizing a clinical trial in humans to test
whether curcumin can prevent the buildup of amyloid plaques that burden
the brains of Alzheimer's patients. If successful, he and his
collaborator (and wife), Sally Frautschy, plan to come up with
formulations that could be mixed in cooking oil (to enhance
bioavailability) and eaten as part of a meal to impede plaque
accumulation--a recipe that might be affordable for both rich and poor
in an aging world.

===