Background: Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk–benefit balances and biologic mechanisms need to be better defined; to further this aim, we used a metabolomics approach.
Methods: We metabolically profiled 40 healthy, nonsmoking men and women ages 20 to 45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/day over a period of 60 days. Gas and liquid chromatography–mass spectrometry were used to comprehensively profile participants' plasma samples after aspirin and placebo interventions.
Results: A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared with placebo-treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (R+S) decreased after aspirin treatment in both men and women (P = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirin-induced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid–oxoacid transhydrogenase mediated production of (R)-2-hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate.
Conclusions: Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)-2-hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention.
Impact: Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non–COX-inhibition-mediated mechanism of aspirin. Cancer Epidemiol Biomarkers Prev; 1–8. ©2015 AACR.
Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).
- Received June 29, 2015.
- Revision received October 12, 2015.
- Accepted October 13, 2015.
- ©2015 American Association for Cancer Research.