Form of Chinese herb found
to temper immune system and kill cancer cells
BY KRISTIN WEIDENBACH
Researchers at the School
of Medicine have discovered that a perennial herb used by
the Chinese for hundreds of years to relieve rheumatoid
arthritis symptoms has much more far-reaching medicinal
qualities. The scientists found that the active component
of the herb is a drug that is able to suppress an
overactive immune system, prevent inflammation and kill
cancer cells.
"This is a remarkable
drug that could have a remarkable future," said
Peter Kao, MD, PhD, assistant professor of pulmonary and
critical care medicine and leader of one of two Stanford
research studies on the drug. Kao's results and those of
Glenn Rosen, MD, also an assistant professor in the
department and lead researcher of the other study, were
published in the May 7 issue of the Journal of
Biological Chemistry.
People have known for 20
years that preparations from Tripterygium Wilfordii
hook, a vine that grows in Southern China, have
medicinal properties, but the way that the herb worked
inside the body was not previously known, said both
researchers. Using a pure preparation of triptolide, the
active compound within the plant, the Stanford scientists
have found that the drug exerts its effects by preventing
activation of a DNA-binding protein, NF-KB, after it has
partnered with its DNA target. This protein is a pivotal
molecule that, once active, escalates an immune response
by switching on other immunologically important genes.
Figuring out exactly how the drug works on a molecular
scale has assisted the two research teams in their
efforts to determine the cause of the biological effects
valued by Tripterygium users.
Dampening the immune
system
Kao's group studied
interactions between triptolide and other immunologically
significant molecules and genes. His lab focuses on drugs
known as immunosuppressants. These are drugs that rein in
the cells of the immune system and prevent them from
inappropriately attacking other cells of the body, as in
the case of autoimmune diseases, or attacking cells that
have been therapeutically introduced into the body, as in
the case of organ transplants. Kao and his colleagues
have found that the way triptolide tempers the immune
system is completely different than the way traditional
immunosuppressants, such as cyclosporin A and FK506,
work. These drugs are prescribed to transplant patients
to prevent their immune systems from rejecting a new
kidney, heart or bone marrow.
Theoretically, these
immunosuppressants can also be given to people suffering
from autoimmune or inflammatory diseases where the immune
system has gone awry. In practice, however, the severe
adverse side effects of these drugs prevent their use in
patients whose conditions are not life threatening.
Because triptolide works in a different way, it may prove
to be a useful alternative.
"Our work shows that
[triptolide] is more potent than more traditional
immunosuppressants such as cyclosporin and FK506,"
said Kao. He sees promise in using triptolide to temper
the immune system and treat patients suffering from graft
vs. host disease, inflammatory diseases like rheumatoid
arthritis, and autoimmune diseases like multiple
sclerosis.
An anti-cancer weapon
Rosen's determination of
the tumor-killing properties of triptolide was more
serendipitous. "We were trying to find ways to
improve the ability to kill solid tumor cells like those
found in the breast, lung and colon," said Rosen,
who was primarily searching for agents that would augment
killing of tumor cells by a class of compounds related to
tumor necrosis factor (TNF). The new drug, triptolide,
cooperates with TNF to cause cancerous cells to die. But
Rosen and his colleagues soon discovered that triptolide
is also capable of killing tumor cells on its own.
"Some tumor cells are
susceptible on their own to triptolide or members of the
TNF family but those that are resistant to one or the
other can be made susceptible to the combination,"
said Rosen.
Triptolide and TNF-like
compounds kill tumor cells by forcing them to commit
suicide a process known as apoptosis, according to
Rosen. However, TNF and related molecules are themselves
toxic to cells and can cause nasty side effects in
patients. Because triptolide does not activate the NF-KB
molecule, these side effects are expected to be greatly
reduced in cancer patients treated with the herbal drug,
he said.
Rosen's optimism about the
drug is bolstered by the fact that triptolide, like the
popular anti-cancer drug taxol, which comes from the bark
of the Pacific Yew tree, kills cancer cells independent
of the p53 gene. Chemotherapy to treat solid tumors is
often hindered because cancer cells frequently become
resistant to the drugs being used. A common cause of this
drug resistance is changes to the p53 tumor suppressor
gene. By causing tumor cells to die in a p53-independent
way, drugs like taxol and triptolide are able to kill
cells from cancers that are found to be resistant to
other chemotherapy agents.
Rosen's research team
includes Kao; Wen-teh Chang, PhD; Kye Young Lee, PhD; and
Daoming Qiu, PhD. Scientists who collaborated on Kao's
study include Qiu; Guohua Zhao, PhD; Yosuke Aoki, PhD;
Lingfang Shi, PhD; and medical school graduate students
Anne Uyei, Saman Nazarian and James Ng.
The pure preparations of
triptolide used in both studies were provided by
Pharmagenesis, Inc., of Palo Alto, Calif. Rosen's study
was supported by a California Breast Cancer Research
Grant and gifts from Pharmagenesis and Jan DiCarli.
Funding for Kao's study was provided by grants from the
National Institutes of Health and gifts from
Pharmagenesis and the Donald E. and Delia B. Baxter
Foundation. SR
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