Degradation of HER2/neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/neu-overexpressing breast cancer cells

FEBS Lett. 2005 Jan 3;579(1):145-52. doi: 10.1016/j.febslet.2004.11.061.


We have shown that exposure of the HER2/neu-overexpressing breast cancer cells to apigenin resulted in induction of apoptosis by depleting HER2/neu protein and, in turn, suppressing the signaling of the HER2/HER3-PI3K/Akt pathway. Here, we examined whether inhibition of this pathway played a role in the anti-tumor effect. The results revealed that treatment with apigenin induced apoptosis through cytochrome c release and caused a rapid induction of caspase-3 activity and stimulated proteolytic cleavage of DFF-45. Furthermore, apigenin downregulated cyclin D1, D3 and Cdk4 and increased p27 protein levels. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in HER2/neu-overexpressing breast cancer cells in the presence of apigenin. In addition, a structure-activity relationship study indicated that (1) the position of B ring; and (2) the existence of the 3', 4'-hydroxyl group on the 2-phenyl group were important for the depletion of HER2/neu protein by flavonoids. These results provided new insights into the structure-activity relationship of flavonoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apigenin / pharmacology*
  • Apoptosis*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism*
  • Caspase 3
  • Caspases / metabolism*
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / analysis
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cyclin D1 / analysis
  • Cyclin D1 / metabolism
  • Cyclin D3
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / analysis
  • Cyclins / metabolism
  • Cytochromes c / metabolism*
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Humans
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteins / metabolism
  • Receptor, ErbB-2 / metabolism*
  • Tumor Suppressor Proteins / analysis
  • Tumor Suppressor Proteins / metabolism


  • CCND3 protein, human
  • Cell Cycle Proteins
  • Cyclin D3
  • Cyclins
  • DNA fragmentation factor, human
  • Flavonoids
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteins
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Apigenin
  • Cytochromes c
  • Receptor, ErbB-2
  • CASP3 protein, human
  • Caspase 3
  • Caspases