title: The arylhydrocarbon receptor is only marginally involved in the antileukemic effects of its ligand curcumin.
abstract: BACKGROUND
  Acute myeloid leukaemia (AML) continues to present demanding treatment challenges, as in general the prognosis for long-term survival remains dire for the patients. Natural plant-derived substances with antileukemic properties offer new treatment possibilities or may act as by-stander therapy. Their molecular mechanisms of action are often not entirely clear, limiting theory-directed screening and application strategies. The plant substance curcumin is a known activator of the transcription factor aryl hydrocarbon receptor (AhR), and has well-documented antileukemic effects. The AhR regulates cell processes, including cell cycle and apoptosis. We ask here whether direct AhR-activation by curcumin contributes to its antileukemic/apoptotic potential.
  
  
  METHODS
  The induction of caspases 3/7, 8, and 9, the breakdown of mitochondrial transmembrane potential, the BCL-2/BAX ratio, and the DNA content of cells were measured as indicators of apoptosis. In addition, the induction of cell cycle inhibitors p21 and p27 were assessed.
  
  
  RESULTS
  While triggering of AhR signalling by curcumin in HL-60 cells was confirmed, induction of the above apoptosis parameters was not blocked by two AhR antagonists, alpha-naphtoflavone (alphaNF) and 3'-methoxy-4'nitroflavone (MNF). Only a moderate (20%) AhR-dependent induction of caspases 3/7 was detectable. Interestingly, transcriptional changes induced by curcumin and by anticarcinogenic 1,25-dihydroxy vitamin D3 overlapped by one third.
  
  
  CONCLUSIONS
  We conclude that AhR is only marginally involved in the antileukemic effects of its ligand curcumin.
authors.affiliation: Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Goergens
authors.forename: Markus
authors.initials: M
authors.lastname: Frericks
authors.forename: Charlotte
authors.initials: C
authors.lastname: Esser
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D001571:Benzoflavones / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C091768:3'-methoxy-4'-nitroflavone; D001571:Benzoflavones; D005419:Flavonoids; D007527:Isoenzymes; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; C011512:alpha-naphthoflavone; D020169:Caspases; D003474:Curcumin