Vitamin E and rutin synergistically inhibit expression of vascular endothelial growth factor through down-regulation of binding activity of activator protein-1 in human promyelocytic leukemia (HL-60) cells

Chem Biol Interact. 2010 Feb 12;183(3):434-41. doi: 10.1016/j.cbi.2009.12.007. Epub 2009 Dec 16.


Reactive oxygen species (ROS) are strong inducers of the angiogenic hormone vascular endothelial growth factor (VEGF). Although, rutin (R) in combination with vitamin E (VE) has been shown to synergistically inhibit oxidative damage, it is unclear whether the combination of R and VE (R+VE) inhibits VEGF secretion in tumor cells. Using a human promyelocytic leukemia (HL-60) cell line, we showed that R in combination with VE synergistically decreased the expressions of VEGF protein and mRNA. We also demonstrated that R+VE significantly decreased the binding capacity of nuclear factor-activator protein-1 (AP-1) to the VEGF gene promoter and decreased the expression of c-Jun protein. Furthermore, we demonstrated that R+VE synergistically reduced insulin receptor substrate-1 (IRS-1) protein expression in HL-60 cells. The decrease of ROS was only partially associated with the decrease of VEGF secreted (r(2)=0.12, P=0.083). Thus, the present results indicate that R in combination with VE attenuates VEGF expression in HL-60 cells and that this effect is mediated by a decreased binding activity of AP-1 through down-regulation of protein expression of insulin-like growth factor 1 receptor (IGF1-R)/IRS-1, while the antioxidant activity of R+VE appears to play a minor role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antioxidants / pharmacology*
  • Down-Regulation
  • Drug Synergism
  • HL-60 Cells
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor, IGF Type 1 / metabolism
  • Rutin / pharmacology*
  • Transcription Factor AP-1 / metabolism*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vitamin E / pharmacology*


  • Antioxidants
  • Insulin Receptor Substrate Proteins
  • Proto-Oncogene Proteins c-jun
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • Vascular Endothelial Growth Factor A
  • Vitamin E
  • Rutin
  • Receptor, IGF Type 1