Molecular targets of aspirin and cancer prevention

Abstract

Salicylates from plant sources have been used for centuries by different cultures to treat a variety of ailments such as inflammation, fever and pain. A chemical derivative of salicylic acid, aspirin, was synthesised and mass produced by the end of the 19th century and is one of the most widely used drugs in the world. Its cardioprotective properties are well established; however, recent evidence shows that it can also act as a chemopreventive agent. Its antithrombotic and anti-inflammatory actions occur through the inhibition of cyclooxygenases. The precise mechanisms leading to its anticancer effects are not clearly established, although multiple mechanisms affecting enzyme activity, transcription factors, cellular signalling and mitochondrial functions have been proposed. This review presents a brief account of the major COX-dependent and independent pathways described in connection with aspirin's anticancer effects. Aspirin's unique ability to acetylate biomolecules besides COX has not been thoroughly investigated nor have all the targets of its primary metabolite, salicylic acid been identified. Recent reports on the ability of aspirin to acetylate multiple cellular proteins warrant a comprehensive study to investigate the role of this posttranslational modification in its anticancer effects. In this review, we also raise the intriguing possibility that aspirin may interact and acetylate cellular molecules such as RNA, and metabolites such as CoA, leading to a change in their function. Research in this area will provide a greater understanding of the mechanisms of action of this drug.

Figure 1

Aspirin chemical reactivity. (A) Aspirin can easily enter cells and react with many different cellular chemicals. For example, aspirin can react with water to form the hydrolysis byproduct salicylic acid. Aspirin can also react with nucleophilic metabolites (e.g., glutathione) or proteins to produce acetylated products. (B) Aspirin can bind to enzyme active sites and modify nucleophilic functional groups. For example in COX-1 aspirin acetylates SER530, rendering the enzyme inactive. (C) Schematic of activity-based profiling to understand sites of acetylation on aspirin. In this experiment, aspirin acetylates active site nucleophilic amino acids. Then the pool of proteins is incubated with activity-based probes to reveal catalytically inactive functional groups, within the now-dead enzymes.

Figure 2

Aspirin reactivity with RNA. (A) Aspirin reacts with serine hydroxyl groups in the active site of enzymes. This acetylation renders the enzyme inactive. (B) RNA acetylation can be performed by introducing electrophiles into cells. In this case reactivity of 2′-OH groups is facilitated by RNA structure and the proximity of the 2′-OH to the phosphate backbone. (C) Chemical reaction between aspirin and RNA, acetylating RNA 2′-OH groups.

Figure 3

Potential of aspirin to acetylate Acetyl-CoA. (A) Chemical structure of acetyl-CoA. (B) Schematic demonstrating the possibility that aspirin acetylation keeps a high steady state level of acetyl-CoA in the cell, through a chemical recycling mechanism.