The arylhydrocarbon receptor is only marginally involved in the antileukemic effects of its ligand curcumin

Anticancer Res. 2009 Nov;29(11):4657-64.

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.

Materials and 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.

Conclusion: We conclude that AhR is only marginally involved in the antileukemic effects of its ligand curcumin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Apoptosis / drug effects
  • Benzoflavones / pharmacology
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Curcumin / pharmacology*
  • Enzyme Activation / drug effects
  • Flavonoids / pharmacology
  • HL-60 Cells
  • Humans
  • Isoenzymes / metabolism
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / pathology
  • Ligands
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / antagonists & inhibitors
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • 3'-methoxy-4'-nitroflavone
  • Benzoflavones
  • Flavonoids
  • Isoenzymes
  • Ligands
  • Receptors, Aryl Hydrocarbon
  • alpha-naphthoflavone
  • Caspases
  • Curcumin