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Senior Citizen Health & Medicine
Cancer-Killing Substance in Tree Bark Could Lead to
New Lung Cancer Treatment
Beta-lapachone is already being used in a clinical
trial to examine its effectiveness against pancreatic cancer in humans
June 26, 2007 – A substance derived from the bark
of the South American lapacho tree kills certain kinds of cancer cells,
and new findings by researchers at UT Southwestern Medical Center have
determined how it works and see it as a possible treatment for the most
common type of lung cancer.
Lung cancer is the number one killer of men and
women in the U.S.
The compound, called beta-lapachone, has shown
promising anti-cancer properties and is currently being used in a
clinical trial to examine its effectiveness against pancreatic cancer in
humans. Until now, however, researchers didn’t know the mechanism of how
the compound killed cancer cells.
Dr. David Boothman, a professor in the Harold C.
Simmons Comprehensive Cancer Center and senior author of a study
appearing online this week in the Proceedings of the National Academy of
Sciences, has been researching the compound and how it causes cell death
in cancerous cells for 15 years.
In the new study, Dr. Boothman and his colleagues
in the Simmons Cancer Center found that beta-lapachone interacts with an
enzyme called NQO1, which is present at high levels in non-small cell
lung cancer and other solid tumors. In tumors, the compound is
metabolized by NQO1 and produces cell death without damaging
noncancerous tissues that do not express this enzyme.
“Basically, we have worked out the mechanism of
action of beta-lapachone and devised a way of using that drug for
individualized therapy,” said Dr. Boothman, who is also a professor of
pharmacology and radiation oncology.
In healthy cells, NQO1 is either not present or is
expressed at low levels. In contrast, certain cancer cells – like
non-small cell lung cancer – over express the enzyme. Dr. Boothman and
his colleagues have determined that when beta-lapachone interacts with
NQO1, the cell kills itself.
Non-small cell lung cancer is the most common type
of lung cancer.
Beta-lapachone also disrupts the cancer cell’s
ability to repair its DNA, ultimately leading to the cell’s demise.
Applying radiation to tumor cells causes DNA damage, which results in a
further boost in the amount of NQO1 in the cells.
“When you irradiate a tumor, the levels of NQO1 go
up,” Dr. Boothman said. “When you then treat these cells with
beta-lapachone, you get synergy between the enzyme and this agent and
you get a whopping kill.”
In the current study, Dr. Boothman tested dosing
methods on human tumor cells using a synthesized version of
beta-lapachone and found that a high dose of the compound given for only
two to four hours caused all the NQO1-containing cancer cells to die.
Understanding how beta-lapachone works to
selectively kill chemotherapy-resistant tumor cells creates a new
paradigm for the care of patients with non-small cell lung cancer, the
researchers said. They are hoping that by using a drug like
beta-lapachone, they can selectively target cancer tumors and kill them
more efficiently. The current therapy for non-small cell lung cancer
calls for the use of platinum-based drugs in combination with radiation.
“Future therapies based on beta-lapachone and NQO1
interaction have the potential to play a major role in treating
devastating drug-resistant cancers such as non-small cell lung cancer,”
said Dr. Erik Bey, lead author of the study and a postdoctoral
researcher in the Simmons Cancer Center. “This is the first step in
developing chemotherapeutic agents that exploit the proteins needed for
a number of cellular processes, such as DNA repair and programmed cell
death.”
About 85 percent of patients with non-small cell
lung cancer have cancer cells containing elevated levels of the NQO1
enzyme, which is produced by a certain gene. Patients who have a
different version of the gene would likely not benefit from treatment
targeting NQO1, Dr. Boothman said.
Dr. Boothman cautioned that clinical trials of
beta-lapachone in lung cancer patients will be needed to determine its
effectiveness as a treatment. He and his team have created a simple
blood test that would screen patients for the NQO1 enzyme.
Along with Dr. Jinming Gao’s laboratory in the
Simmons Cancer Center and a joint collaboration with the bioengineering
program at UT Dallas, researchers in the new “Cell Stress and Cancer
Nanomedicine” initiative within the Simmons Cancer Center have developed
novel nanoparticle drug delivery methods for the tumor-targeted delivery
of this compound. These delivery methods have the promise of further
improving this drug for non-small cell lung cancer.
Other Simmons Cancer Center researchers involved in
the study were Dr. Ying Dong, postdoctoral researcher; Dr. Chin-Rang
Yang, assistant professor; and Dr. Gao, associate professor. UT
Southwestern’s Dr. John Minna, director of the Nancy B. and Jake L.
Hamon Center for Therapeutic Oncology Research and the W.A. “Tex” and
Deborah Moncrief Jr. Center for Cancer Genetics, and Dr. Luc Girard,
assistant professor of pharmacology, also participated along with
researchers from Case Western Reserve University and UT M.D. Anderson
Cancer Center.
The research was supported by the National
Institutes of Health.
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