In numerous studies, use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been demonstrated to reduce colon cancer risk.1,2
At doses of at least 75 mg/day, aspirin reduces the 20-year risk of colon cancer but not of rectal cancer, with the effect most pronounced for cancer of the proximal colon and closely associated with longer duration of use. Use of aspirin for at least 5 years leads to an approximately 70% reduction in risk of proximal colon cancer.3
Despite the concrete evidence of risk reduction, the exact mechanism by which NSAIDs prevent tumorigenesis has remained elusive. Now researchers led by Lin Zhang, PhD, associate professor of pharmacology and chemical biology at the University of Pittsburgh Cancer Institute in Pittsburgh, PA, have identified the mechanism by which NSAIDs prevent colon cancer.
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In the November issue of Proceedings of the National Academy of Science they report that NSAIDs cause genetically mutated, precancerous intestinal stem cells to self destruct.2 “Our study shows that NSAIDs target stem cells that have accumulated mutations that could lead to cancer development,” Dr. Zhang said. The NSAIDs “initiate a biochemical pathway that leads to apoptosis.”
The study used mice with a genetic defect that leads to APC deficiency, a defect in the tumor suppressor pathway similar to that seen in individuals with familial adenomatous polyposis and a driver of many non-hereditary colon and rectal cancers as well.2
In the study, apoptosis rates in mouse intestinal polyps were strikingly elevated within a week of ingesting the NSAID sulindac. Dr. Zhang noted this apoptosis was specific for APC-deficient intestinal stem cells with accumulated precancerous changes.
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With further study, the researchers concluded that BID, a BH3-only Bcl-2 family member that mediates cross talk between extrinsic (ie, death receptor) and intrinsic (ie, mitochondrial) apoptosis pathways, was crucial to NSAID-related tumor cell suppression, selectively neutralizing APC-deficient cells.2
Extrinsically, BID is activated by NSAIDs and then engages intrinsic pathways to induce apoptosis. Intrinsically, BID is involved in release of key apoptosis pathway mediators, and its absence undermines the process. In BID-knockout mice, lack of BID prevented cytosolic release of SMAC (also known as DIABLO), a protein that enhances cell apoptosis by binding with inhibitor of apoptosis proteins (IAP).4
Further, NSAID-induced stem cell apoptosis was attenuated in SMAC-deficient cells, suggesting an important role for the protein, according to Dr Zhang.2
The researchers also looked at tissue samples of adenomas from patients who did or did not use NSAIDs. Their findings confirmed that BID activation and apoptosis rates among oncogenic stem cells were higher among patients taking NSAIDs.2
Of course, any clinical role for NSAIDs in prevention of colon cancer must take into account the potential for cardiovascular and gastrointestinal adverse effects of the drugs.
Cancers of the colon and rectum are increasingly common as populations worldwide become more developed and industrialized.
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In 2014, cancers of the colon and rectum will be diagnosed in more than 136,000 Americans. Although mortality from these cancers has declined with new approaches to treatment, they remain the third leading cause of cancer death in both men and women.5
Dr. Zhang said that the clinical implications of the researchers’ finding include the potential to develop chemoprevention agents to sensitize abnormal stem cells to NSAID-induced apoptosis while avoiding the harms associated with NSAID use.
References
- Crosara Teixeira M, Braghiroli MI, Sabbaga J, Hoff PM. Primary prevention of colorectal cancer: myth or reality? World J Gastroenterol. 2014;20(41):15060-15069.
- Leibowitz B, Qiu W, Buchanan ME, et al. BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci USA. 2014;111(46):16520-16525.
- Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741-1750.
- National Center for Biotechnology Information. DIABLO diablo, IAP-binding mitochondrial protein. http://www.ncbi.nlm.nih.gov/gene/56616. Updated November 22, 2014. Accessed November 24, 2014.
- American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
