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not-yet-ready for prime-time: aspirin reverses resistance to TRAIL
A news service summary and an abstract:
Pretreating rogue cancer cells with aspirin cripples their resistance to targeted therapy
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.
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# ABSTRACT: Pretreatment of Acetylsalicylic Acid Promotes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis by Down-regulating BCL-2 Gene Expression [Journal of Biological Chemistry; Subscribe]
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selective in the induction of apoptosis in cancer cells with minimal toxicity to normal tissues. However, not all cancers are sensitive to TRAIL-mediated apoptosis. Thus, TRAIL-resistant cancer cells must be sensitized first to become responsive to TRAIL. In this study, we observed that pretreatment by acetylsalicylic acid (ASA) augmented TRAIL-induced apoptotic death in human prostate adenocarcinoma LNCaP and human colorectal carcinoma CX-1 cells. Western blot analysis showed that pretreatment of ASA followed by TRAIL treatment activated caspases (8, 9, and 3) and cleaved poly(ADP-ribose) polymerase, the hallmark feature of apoptosis. Most interestingly, at least 12 h of pretreatment with ASA was prerequisite for promoting TRAIL-induced apoptosis and was related to down-regulation of BCL-2. Biochemical analysis revealed that ASA inhibited NF-?B activity, which is known to regulate BCL-2 gene expression, by dephosphorylating I?B-? and inhibiting IKK? activity but not by affecting the HER-2/neu phosphatidylinositol 3-kinase-Akt signal pathway. Overexpression of BCL-2 suppressed the promotive effect of ASA on TRAIL-induced apoptosis and changes in mitochondrial membrane potential. Taken together, our studies suggested that ASA-promoted TRAIL cytotoxicity is mediated through down-regulating BCL-2 and by decreasing mitochondrial membrane potential.
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