TY - JOUR
T1 - Aspirin reduces plasma concentrations of the oncometabolite 2-hydroxyglutarate
T2 - Results of a randomized, double-blind, crossover trial
AU - Liesenfeld, David B.
AU - Botma, Akke
AU - Habermann, Nina
AU - Toth, Reka
AU - Weigel, Christoph
AU - Popanda, Odilia
AU - Klika, Karel D.
AU - Potter, John D.
AU - Lampe, Johanna W.
AU - Ulrich, Cornelia M.
N1 - Funding Information:
The authors thank Dr. Ross Prentice for statistical advice, Dr. Bert Vogelstein for providing colorectal cancer cell lines, Andrea Breuer for providing rat liver mitochondrial/lysosomal fractions, and the ABC study participants for their time and contribution. This study was supported by the US National Institutes of Health (R01 CA094954; J.W. Lampe, R01 CA112516; C.M. Ulrich, J.D. Potter), the German Consortium for Translation Cancer Research (DKTK; C.M. Ulrich), and institutional funding of theDivision of Preventive Oncology (C.M. Ulrich), National Center for Tumor Diseases, Heidelberg. D.B. Liesenfeld and C. Weigel both received fellowships from the Helmholtz International Graduate School for Cancer Research.
Publisher Copyright:
©2015 AACR.
PY - 2016/1
Y1 - 2016/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84955270177&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-15-0697
DO - 10.1158/1055-9965.EPI-15-0697
M3 - Article
C2 - 26585118
AN - SCOPUS:84955270177
SN - 1055-9965
VL - 25
SP - 180
EP - 187
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 1
ER -