title: 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.
abstract: 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.
authors.affiliation: Department of Food Science and Applied Biotechnology, Hungkuang University, 34 Chung Chie Road, Shalu, Taichung County, Taiwan, Republic of China.
authors.forename: Cheng-Hung
authors.initials: CH
authors.lastname: Chuang
authors.forename: Chin-Shiu
authors.initials: CS
authors.lastname: Huang
authors.forename: Miao-Lin
authors.initials: ML
authors.lastname: Hu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D015536:Down-Regulation; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012431:Rutin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D055504:Insulin Receptor Substrate Proteins; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D014810:Vitamin E; D012431:Rutin; D017526:Receptor, IGF Type 1