Mechanisms of Colorectal Cancer Prevention by Aspirin—A Literature Review and Perspective on the Role of COX-Dependent and -Independent Pathways

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.

Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention

“…Nevertheless, the main anticancer activity of NSAIDs is thought to be a suppression of prostaglandin E 2 synthesis via COX-2 inhibition, which causes a decrease in tumor cell proliferation, angiogenesis, and increases apoptosis [ 36 , 61 ]. Although many of the anticancer mechanisms of NSAIDs are defined as COX-dependent, several signal transduction pathways (e.g., including nuclear factor-kappa B, NF-κB) have been confirmed as COX-independent NSAID-induced effects [ 62 , 63 , 64 , 65 ]. The correlation between the COX expression and colorectal cancer, including prognostic factors and putative chemopreventive agents, has been widely studied worldwide and reviewed in the past [ 66 ].…”

Cell polarity and cell adhesion associated gene expression differences between invasive micropapillary and no special type breast carcinomas and their prognostic significance

“…These molecules have been studied in many cancer types, and their expression profile and localization pattern have been found to differ in normal and tumor tissue as well as in different types of carcinomas. The roles of these molecules in tumor progression and suppression have also been investigated by many groups 13 , 14 . The dysregulation of these molecules occurs during carcinogenesis via different mechanisms.…”

Metabolomic Profiling Identified Serum Metabolite Biomarkers and Related Metabolic Pathways of Colorectal Cancer

“…Our study found that the only diagnostic metabolic biomarker with a downregulated trend in CRC patients compared to healthy controls was 2,3-DHBA. As a metabolite of aspirin and salicylic acid, it has been shown to inhibit colon cancer cell growth [ 33 , 34 ]. A consensus has not been reached on the anticancer mechanisms of 2,3-DHBA.…”