title: Dichloroacetate at therapeutic concentration alters glucose metabolism and induces regulatory T-cell differentiation in alloreactive human lymphocytes.
abstract: BACKGROUND
  Most cancer cells rely on aerobic glycolysis. Dichloroacetate (DCA) inhibits aerobic glycolysis and is a promising relatively nontoxic anticancer compound. However, rapidly proliferating effector T-cells also rely on aerobic glycolysis, whereas regulatory T-cells (Treg) do not. The effect of DCA on glucose metabolism and Treg differentiation was evaluated in alloreactive lymphocytes.
  
  
  METHODS
  Peripheral blood mononuclear cells from healthy volunteers were used in a two-way mixed lymphocyte reaction. Lymphocyte proliferation was assessed by cell counting; DCA cytotoxicity, by lactate dehydrogenase release assay; and glucose uptake and aerobic glycolysis, by measuring in the supernatants the correspondent glucose and lactate concentrations. Interleukin-10 (IL-10) was measured in the supernatants, whereas the Treg signature transcription factor forkhead box P3 (FOXP3) was measured in cell lysates by means of enzyme-linked immunosorbent assay.
  
  
  RESULTS
  DCA had a minor effect on lymphocyte proliferation and cytotoxicity. However, DCA decreased glucose uptake and inhibited aerobic glycolysis. Finally, DCA markedly increased the production of IL-10 and the expression of FOXP3.
  
  
  CONCLUSIONS
  DCA inhibits aerobic glycolysis and induces Treg differentiation in human alloreactive lymphocytes. This could result in decreased immunosurveillance in case of its use as an anticancer drug. However, DCA could play a role as an immunosuppressant in the fields of transplantation and autoimmunity.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Eleftheriadis
authors.forename: Georgios
authors.initials: G
authors.lastname: Pissas
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Karioti
authors.forename: Georgia
authors.initials: G
authors.lastname: Antoniadi
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Antoniadis
authors.forename: Vassilios
authors.initials: V
authors.lastname: Liakopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
mesh_terms: D000332:Aerobiosis; D015551:Autoimmunity / Q000187:drug effects*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D016753:Interleukin-10; D003999:Dichloroacetic Acid; D005947:Glucose