Abstract
Aspirin, synthesized and marketed in 1897 by Bayer, is one of the most widely used drugs in the world. It has a well-recognized role in decreasing inflammation, pain and fever, and in the prevention of thrombotic cardiovascular diseases. Its anti-inflammatory and cardio-protective actions have been well studied and occur through inhibition of cyclooxygenases (COX). Interestingly, a vast amount of epidemiological, preclinical and clinical studies have revealed aspirin as a promising chemopreventive agent, particularly against colorectal cancers (CRC); however, the primary mechanism by which it decreases the occurrences of CRC has still not been established. Numerous mechanisms have been proposed for aspirin’s chemopreventive properties among which the inhibition of COX enzymes has been widely discussed. Despite the wide attention COX-inhibition has received as the most probable mechanism of cancer prevention by aspirin, it is clear that aspirin targets many other proteins and pathways, suggesting that these extra-COX targets may also be equally important in preventing CRC. In this review, we discuss the COX-dependent and -independent pathways described in literature for aspirin’s anti-cancer effects and highlight the strengths and limitations of the proposed mechanisms. Additionally, we emphasize the potential role of the metabolites of aspirin and salicylic acid (generated in the gut through microbial biotransformation) in contributing to aspirin’s chemopreventive actions. We suggest that the preferential chemopreventive effect of aspirin against CRC may be related to direct exposure of aspirin/salicylic acid or its metabolites to the colorectal tissues. Future investigations should shed light on the role of aspirin, its metabolites and the role of the gut microbiota in cancer prevention against CRC.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer related deaths [1,2] and the third most common cancer diagnosis [3] in the United States of America
Colorectal cancer usually begins as a benign adenomatous polyp that develops into an advanced form of adenoma with high-grade dysplasia, which eventually leads to the development of invasive cancer [4]
It is to be noted that aspirin is more selective to COX-1 as compared to COX-2, with IC50 for COX-1 inhibition observed at 1.7 μM compared to the >100 μM required for COX-2 inhibition [39,40]
Summary
Colorectal cancer (CRC) is the second most common cause of cancer related deaths [1,2] and the third most common cancer diagnosis [3] in the United States of America. Numerous epidemiological and clinical studies thereafter proved aspirins’ efficacy to reduce CRC These include (1) observational case-control studies [9,10], (2) randomized control trials in subjects with sporadic colorectal adenomas [11], (3) randomized control trials in subjects with Lynch syndrome [12,13] and (4) individual patient data meta-analysis of random control trials in the prevention of vascular events [14]. These studies indicated a decrease in the occurrence of CRC upon aspirin consumption and the overall incidences of gastrointestinal (GI) cancers in individual cases highly correlated with that of randomized trials [10,14]. The intent of this review is to discuss some of these potential mechanisms reported in the literature and assess their strengths and limitations in light of recently published papers
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