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Research Paper : 04
“Pretreating rogue cancer cells with aspirin cripples their resistance to targeted
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. 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,
"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
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
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
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 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."
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