title: Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial.
abstract: 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.
  
  
  CONCLUSIONS
  Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non-COX-inhibition-mediated mechanism of aspirin.
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David B
authors.initials: DB
authors.lastname: Liesenfeld
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Akke
authors.initials: A
authors.lastname: Botma
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Habermann
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Reka
authors.initials: R
authors.lastname: Toth
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Weigel
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Odilia
authors.initials: O
authors.lastname: Popanda
authors.affiliation: Genomics and Proteomics Core Facility, Molecular Structure Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karel D
authors.initials: KD
authors.lastname: Klika
authors.affiliation: Centre for Public Health Research, Massey University, Wellington, New Zealand. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Lampe
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington. Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah. neli.ulrich@hci.utah.edu.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D000328:Adult; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D005977:Glutarates / Q000097:blood*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors; D011379:Prognosis; D018570:Risk Assessment; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D005977:Glutarates; D024101:Mitochondrial Proteins; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C072878:hydroxyacid-oxoacid transhydrogenase; D001241:Aspirin