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Cancer Cells Self-Destruct from Aspirin with TRAIL
Therapy
Dec. 12, 2005 - For years, we have heard about the
health benefits of taking low doses of aspirin preventing everything
from Alzheimer's disease to heart attacks and stroke. The news about
aspirin just keeps getting better. In a study published in the Dec. 9
issue of the Journal of Biological Chemistry, University of Pittsburgh
researchers report that aspirin, combined with a promising new cancer
therapy known as tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL), can induce cancer cells previously resistant to TRAIL therapy
to self-destruct.
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The investigators say that if these findings hold
up in larger studies, aspirin could become a routine therapy for helping
to prevent the recurrence of many aggressive cancers, such as prostate
and colon cancers.
"When cancers recur after initial therapy, they
tend to be extremely aggressive and patient prognosis is poor," said
Yong J. Lee, Ph.D., professor in the departments of surgery and
pharmacology, University of Pittsburgh School of Medicine, and lead
author of the study.
"If we could find ways to prevent these secondary
cancers from occurring, we could save many lives. Aspirin is a low-cost
medicine that, in our studies, appears to have great potential for
helping to prevent such cancer recurrences."
TRAIL is a protein that is expressed by cells of
the immune system.
Numerous studies have shown that TRAIL induces
programmed cell death, or apoptosis, in cancer cells while having little
or no effect in normal healthy cells. Apoptosis is one of several
mechanisms by which damaged cells self-destruct and is the body's way of
ensuring that only healthy cells reproduce.
Most often, apoptosis eliminates rogue cells with
damaged DNA or cells growing too quickly, but it also eliminates normal
cells that have simply become obsolete as an organism grows and
develops. Because cancer cells have lost their ability to undergo
apoptosis, they continue to reproduce and spread their damaged progeny
throughout the body.
In recent years, scientists have gained an
increasingly sophisticated understanding of the mechanisms of apoptosis,
which has led to the development of a number of therapies targeted to
repairing or bypassing damaged apoptotic processes in cancer cells.
TRAIL is one of the more promising of these agents, and a synthesized
form of TRAIL has been shown in cell cultures and animal models to
induce apoptosis alone and in combination with other drugs.
Unfortunately, studies have found that not all
cancers are sensitive to TRAIL. In fact, many tumor cells are completely
resistant to TRAIL's effects, creating an intensive search for compounds
that can overcome this resistance.
Based on other studies showing that aspirin can
prevent the formation of tumors caused by ultraviolet radiation and
carcinogens, Dr. Lee and his coworkers decided to test the ability of
this compound to increase the sensitivity of TRAIL-resistant cancer
cells to apoptosis.
To do this, they treated human prostate cancer
cells with aspirin and then treated the cells with a combination of
TRAIL and/or aspirin. Cancer cells treated with either aspirin or TRAIL
alone showed little or no cell death. However, pretreatment of the
TRAIL-resistant cancer cells with aspirin promoted cell death when TRAIL
was added.
To determine whether TRAIL was indeed inducing
apoptosis in the aspirin-sensitized cells or killing the cells through
some other mechanism, Dr. Lee and his coworkers looked for molecular
signs of apoptosis. In the cancer cells pretreated with aspirin followed
by TRAIL, there was significant cleavage, or cutting up, of a compound
known as poly (ADP-ribose) polymerase, or PARP. PARP cleavage, a
hallmark feature of apoptosis, did not occur in normal cells nor in
cancer cells treated with aspirin alone.
Interestingly, the investigators discovered that,
for PARP cleavage to occur, it was necessary to pretreat cancer cells
with aspirin at least 12 hours before the administration of TRAIL. Dr.
Lee and his colleagues also found that aspirin treatment causes cancer
cells to decrease their production of a cellular protein known as Bcl-2,
which has been shown in numerous studies to protect healthy cells from
premature apoptosis.
Decreased Bcl-2 production was the result of
suppression of the Bcl-2 gene. Furthermore, when the investigators
induced prostate and colon cancer cells to produce excess amounts of the
Bcl-2 protein in the cells, the cells were still resistant to
TRAIL-induced apoptosis even when they were pretreated with aspirin.
According to Dr. Lee, this suggests that TRAIL induces apoptosis via
cellular mitochondria.
"Bcl-2 inhibits the release of a compound known as
cytochrome c from mitochondria, an organelle in the cell that regulates
energy production as well as cell death. Therefore, we suspected that
TRAIL might be inducing cell death through mitochondria-mediated
apoptosis.
"In this study we demonstrated that aspirin can
down-regulate Bcl-2 gene expression and consequently change the
electrical potential of the mitochondrial membrane in cancer cells,
thereby releasing cytochrome c and other apoptotic proteins."
Dr. Lee and his colleagues believe these findings
could soon be applied in the clinical setting and result in the
increased effectiveness of TRAIL for treating a number of aggressive
cancers, particularly those that overexpress the human epidermal growth
factor receptor 2 (HER-2/neu) gene.
This gene is amplified up to 30 percent in some
human cancers, which leads to an increase in the expression of the
HER-2/neu protein on the cell surface. Numerous studies suggest that a
high concentration of the HER-2/neu protein on the surface of cancer
cells makes them more aggressive and difficult to treat. In this study,
Dr. Lee and coworkers demonstrated that the combination of aspirin and
TRAIL undercuts the effects of HER-2/neu overexpression.
"HER-2/neu overexpression in cancer cells, such as
prostate and colon, is associated with a higher cell proliferation rate,
faster metastases and greater tumor burden," explained Dr. Lee. "It is
our hope that aspirin and other agents we are currently testing can
negate this effect and dramatically improve the prognosis of patients
with these types of cancer."
In addition to Dr. Lee, other contributors to this
study include Kim M. Kim, Ph.D., and Jae J. Song, Ph.D., department of
surgery, University of Pittsburgh School of Medicine, and Jee Young An,
Ph.D., and Yong Tae Kwon, Ph.D., Center for Pharmacogenetics, department
of pharmaceutical sciences, University of Pittsburgh School of Pharmacy.
This study was supported by grants from the
National Cancer Institute, National Institutes of Health, the Elsa U.
Pardee Foundation, The Pittsburgh Foundation, the Department of Defense
Prostate Program Fund and Department of Defense Prostate Traineeship.
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