Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid

Abstract

Given to its ability to irreversibly acetylate the platelet cyclooxygenase-1 enzyme, acetylsalicylic acid (ASA) is successfully employed for the prevention of cardiovascular disease. Recently, an antitumoral effect of ASA in colorectal cancer has been increasingly documented. However, the molecular and metabolic mechanisms by which ASA exerts such effect is largely unknown. Using a new, untargeted liquid chromatography–mass spectrometry approach, we have analyzed urine samples from seven healthy participants that each ingested 100 mg of ASA once daily for 1 week. Of the 2007 features detected, 25 metabolites differing after ASA ingestion (nominal p < 0.05 and variable importance in projection (VIP) score > 1) were identified, and pathway analysis revealed low levels of glutamine and of metabolites involved in histidine and purine metabolisms. Likewise, consistent with an altered fatty acid β-oxidation process, a decrease in several short- and medium-chain acyl-carnitines was observed. An abnormal β-oxidation and a lower than normal glutamine availability suggests reduced synthesis of acetyl-Co-A, as they are events linked to one another and experimentally related to ASA antiproliferative effects. While giving an example of how untargeted metabolomics allows us to explore new clinical applications of drugs, the present data provide a direction to be pursued to test the therapeutic effects of ASA—e.g., the antitumoral effect—beyond cardiovascular protection.

Effective Aspirin Treatment of Women at Risk for Preeclampsia Delays the Metabolic Clock of Gestation

“…We were able to detect many of the metabolites in aspirin-related pathways profiled in previous studies on other diseases, such as downregulated metabolites in glutamate and histidine metabolism pathways 35,36 and decreased LC-PUFA dihomo-linolenate (20:3n3 or n6; HMDB0002925) in oxylipid synthesis. 37 At the same time, we also found metabolic changes that were less often linked to aspirin, for example, an increase of arachidonic acid-containing lipids including lysophospholipid, phosphatidylcholine, and phosphatidylinositol (Figure 1C, Table S3).…”

DDIT4 Downregulation by siRNA Approach Increases the Activity of Proteins Regulating Fatty Acid Metabolism upon Aspirin Treatment in Human Breast Cancer Cells

“…The authors suggested that the metabolic outcome of aspirin in vivo may depend on the expression of thioesterases that hydrolyze acetylsalicylic acid (aspirin) to salicylic acid since they found an opposite effect of salicylic acid on 3H-palmitate oxidation. Aspirin-mediated activation of fatty acid oxidation was further confirmed through the analysis of human urine samples collected after 7 days of aspirin treatment [ 50 ]. Promotion of FA oxidation upon aspirin treatment is consistent with the reported AMPK activation and resulting deactivation of ACC [ 46 , 47 ], because the catalytic product of ACC2 isoform malonyl-CoA is the natural inhibitor of CPT1A [ 28 , 51 ].…”

Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation

“…Liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) analysis was performed using ultra-highperformance liquid chromatography system (1290 InfinityII; Agilent) coupled to a quadrupole time-of-flight mass spectrometry detector (6545; Agilent) outfitted with an electrospray ionization (ESI) source. LC-QTOF-MS method, performance evaluation, data processing, and acyl-carnitine identification and analysis were performed as a published report with minor modifications (48). In brief, a sample (2 μL) was injected into Waters XSelect HSS T3 chromatographic column (2.5 μm; 100 × 2 mm), maintained at 25 °C.…”