Jayarama B. Gunaje, Ph.D., is associate professor, Department of Pharmaceutical Sciences, at the South Dakota State University College of Pharmacy in Brookings, S.D.
Aspirin is extensively used for its anti-inflammatory, analgesic, and antithrombotic effects. Interestingly, several epidemiological studies show that regular intake of aspirin for 5 years or more decreases the incidence of colon cancer by 40%. Aspirin’s use after the colorectal cancer diagnosis lowers the risk and increases patient survival. Cancer risk reduction was also observed in distal organs such as breast, lung, and prostate tissue. A more recent study showed that people who reported using aspirin for 5 years or more had a 20% lower risk of developing melanoma. Thus, several evidences suggest that aspirin, a common household drug, can act as a chemo-preventive agent.
The acetyl and salicylate groups present in aspirin have distinct protein targets. While the salicylate group has been implicated in the anti-inflammatory properties of aspirin via inhibition of NF-kB (nuclear factor kappa B) transcription factor, the acetyl group acetylates cyclooxygenases (COXs) to inhibit the enzyme activity. There are mainly 2 isoforms of COX; COX-1 expression is constitutively detected in gastric mucosa and other tissues; however, COX-2, which is an inducible enzyme, is detected after exposure of cells to cytokines, or bacterial lipopolysaccharides, or infections. Cyclooxygenases synthesize prostaglandins important in inflammatory responses that occur after injury and wound healing. Research also suggests that uncontrolled tissue inflammation can lead to cancerous state in tissues including the colon. Most human colon cancer tissue show elevated levels of COX-2, and this has been shown to correlate well with tumor progression. In people who are at higher risk of developing colon cancer, inhibition of COX-2 with inhibitors protected against precancerous colon polyps. Therefore, it is believed that, aspirin’s ability to reduce colorectal cancer occurs at least in part, via inhibition of the COX-2 activity.
Aspirin’s ability to reduce cancer has not only been discussed frequently in scientific literature but also in the news media. Despite the diverse mechanisms proposed for the chemo-preventive properties of aspirin, the most important protein targets of its action are still not clear. Besides COX, it is not clear whether aspirin acetylates other proteins to modulate their activity and to exert its anticancer effects. Similarly, beside NF-kB, novel protein targets may also exist for aspirin’s primary metabolite, salicylic acid, which may also contribute to its anti-cancer effects.
Studies from our laboratory show that aspirin exposure to colon cancer cells causes acetylation of a variety of proteins. These include cytoskeletal proteins, histones, ribosomal, and mitochondrial proteins. One interesting protein we are currently analyzing for its role in aspirin’s anti-cancer effects is the tumor suppressor protein p53, which is mutated and inactivated in nearly 50% of tumors. Elucidating the role of p53 or other key protein targets of aspirin, or its metabolite, salicylic acid, would provide a greater understanding of its anti-cancer effects.
What do you think are the likely direct protein targets of aspirin or its metabolite, salicylic acid, that are important for its anti-cancer effects (beside COX and NF-kB)?