Anthocyanidins induce apoptosis in human promyelocytic leukemia cells: structure-activity relationship and mechanisms involved

Int J Oncol. 2003 Sep;23(3):705-12.


Anthocyanidins are the aglycon nucleuses of anthocyanins, which are reddish pigments widely spread in colored fruits and vegetables. To investigate their anti-cancer effect, induction of apoptosis was tested in human promyelocytic leukemia cells (HL-60), which is a valid model for testing antileukemic or general antitumoral compounds. Of six anthocyanidins representing the aglycons of most of anthocyanins, only those with an ortho-dihydroxyphenyl structure on the B-ring induce apoptosis, suggesting that the ortho-dihydroxyphenyl structure of anthocyanidins may contribute to the induction of apoptosis. Delphinidin, the most potent inducer, causes apoptosis in a time- and dose-dependent manner. The efficacious induction of apoptosis was observed at 100 micro M for 6 h. Concomitant with the apoptosis, delphinidin stimulates JNK pathway activation including JNK phosphorylation and c-jun gene expression, and activates caspase-3. Antioxidants including N-acetyl-L-cysteine (NAC) and catalase effectively block delphinidin-induced JNK phosphorylation, caspase-3 activation, and DNA fragmentation. Moreover, anthocyanidins directly cause HL-60 cells to generate intracellular hydrogen peroxide. Thus, anthocyanidins may trigger an apoptotic death program through an oxidative stress-involved JNK signaling pathway. The induction of apoptosis by anthocyanins may be the pivotal mechanism by which its chemopreventive action against cancer is based.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Anthocyanins / chemistry
  • Anthocyanins / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis*
  • Blotting, Western
  • Caspase 3
  • Caspases / metabolism
  • DNA Fragmentation
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • HL-60 Cells
  • Humans
  • Hydrogen Peroxide / metabolism
  • Leukemia, Promyelocytic, Acute / pathology*
  • Models, Chemical
  • Oxidative Stress
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Structure-Activity Relationship
  • Time Factors


  • Anthocyanins
  • Antioxidants
  • Proto-Oncogene Proteins c-jun
  • RNA
  • Hydrogen Peroxide
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • delphinidin
  • Acetylcysteine