Pretreating rogue cancer cells with aspirin cripples their resistance to targeted therapy

December 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. 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.

University of Pittsburgh Medical Center

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