Do Aspirin and Flavonoids Prevent Cancer through a Common Mechanism Involving Hydroxybenzoic Acids?-The Metabolite Hypothesis

Abstract

Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately pinpoint the mechanism involved is due to the failure to differentiate the primary targets from its associated downstream responses. This review is written in the context of the recent findings on the potential pathways involved in the prevention of colorectal cancers (CRC) by aspirin and flavonoids. Recent reports have demonstrated that the aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,5-dihydroxybenzoic acid (2,5-DHBA) and the flavonoid metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA) and 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) were effective in inhibiting cancer cell growth in vitro. Limited in vivo studies also provide evidence that some of these hydroxybenzoic acids (HBAs) inhibit tumor growth in animal models. This raises the possibility that a common pathway involving HBAs may be responsible for the observed cancer preventive actions of aspirin and flavonoids. Since substantial amounts of aspirin and flavonoids are left unabsorbed in the intestinal lumen upon oral consumption, they may be subjected to degradation by the host and bacterial enzymes, generating simpler phenolic acids contributing to the prevention of CRC. Interestingly, these HBAs are also abundantly present in fruits and vegetables. Therefore, we suggest that the HBAs produced through microbial degradation of aspirin and flavonoids or those consumed through the diet may be common mediators of CRC prevention.

Keywords: CDKs; aspirin; cancer prevention; cell cycle; colorectal cancer; flavonoids; hydroxybenzoic acids.

Figure 1

Classical pathways and cellular targets known to be affected by aspirin and flavonoids, leading to the prevention of various cancers. Aspirin and flavonoids affect numerous molecular pathways, some of which overlap. Pathways affected by aspirin alone are indicated in the left, shared pathways are shown in the middle, while pathways affected by flavonoids are shown in the right [6,13,14,33,34,35,36,37,38,39,40,41,42].

Figure 2

Metabolism of aspirin and flavonoids to generate hydroxybenzoic acids. (A) Aspirin metabolism generates 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-DHBA through CYP450 reactions in the liver [61]. DHBAs have also been shown to be generated through microbial metabolism of aspirin/salicylic acid [12]. (B) Flavonoid metabolism generates metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-DHBA, 3,4,5-THBA, 4-HBA, 2,4-DHBA, 2,6-DHBA through microbial degradation in the intestine [11,45,56,58]. R-R5 represent various functional groups (example -hydroxy, -ketone, -hydrogen, -methoxy, etc.) that are appended/attached to the flavonoid backbone to generate different groups of flavonoids.

Figure 3

Metabolite hypothesis: Model depicting convergence of the pathways generating HBAs from parent compounds through host/microbial enzymes. We propose that actions of HBAs, generated through biotransformation of aspirin and flavonoids, retard rate of cell proliferation. This would provide an opportunity for (i) immune surveillance, leading to the destruction of cancer cells, or (ii) DNA repair in cells containing damaged DNA, providing genetic stability, both of which are important steps in the prevention of cancer. While 2,4,6-THBA is likely to retard cell proliferation through CDK inhibition and upregulation of p21^Cip1 and p27^Kip1, the exact mechanisms of cell growth inhibition by other HBAs is still not understood [57,63]. EGCG—Epigallocatechin gallate, C3G—Cyanidin-3-glucoside.