title: Novel PI3K/AKT targeting anti-angiogenic activities of 4-vinylphenol, a new therapeutic potential of a well-known styrene metabolite.
abstract: The pneumo- and hepato-toxicity of 4-vinylphenol (4VP), a styrene metabolite, has been previously reported. Nevertheless, the present study reported the novel anti-angiogenic activities of 4VP which was firstly isolated from the aqueous extract of a Chinese medicinal herb Hedyotis diffusa. Our results showed that 4VP at non-toxic dose effectively suppressed migration, tube formation, adhesion to extracellular matrix proteins, as well as protein and mRNA expressions of metalloproteinase-2 of human endothelial cells (HUVEC and HMEC-1). Investigation of the signal transduction revealed that 4VP down-regulated PI3K/AKT and p38 MAPK. Besides, 4VP interfered with the phosphorylation of ERK1/2, the translocation and expression of NFkappaB. In zebrafish embryo model, the new blood vessel growth was significantly blocked by 4VP (6.25-12.5 μg/mL medium). The VEGF-induced blood vessel formation in Matrigel plugs in C57BL/6 mice was suppressed by 4VP (20-100 μg/mL matrigel). In addition, the blood vessel number and tumor size were reduced by intraperitoneal 4VP (0.2-2 mg/kg) in 4T1 breast tumor-bearing BALB/c mice, with doxorubicin as positive control. Together, the in vitro and in vivo anti-angiogenic activities of 4VP were demonstrated for the first time. These findings suggest that 4VP has great potential to be further developed as an anti-angiogenic agent.
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Grace Gar-Lee
authors.initials: GG
authors.lastname: Yue
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Julia Kin-Ming
authors.initials: JK
authors.lastname: Lee
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Hin-Fai
authors.initials: HF
authors.lastname: Kwok
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Ling
authors.initials: L
authors.lastname: Cheng
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Eric Chun-Wai
authors.initials: EC
authors.lastname: Wong
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Hoi-Wing
authors.initials: HW
authors.lastname: Leung
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Yuk-Lau
authors.initials: YL
authors.lastname: Wong
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Leung
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [3] School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: 1] Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong [2] State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Clara Bik-San
authors.initials: CB
authors.lastname: Lau
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D032064:Hedyotis / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000096:biosynthesis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010636:Phenols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013343:Styrenes / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D015027:Zebrafish; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C534699:CCNB1 protein, human; C530104:CCND1 protein, human; D056744:Cyclin B1; D004365:Drugs, Chinese Herbal; D016326:Extracellular Matrix Proteins; D016328:NF-kappa B; D010636:Phenols; D010936:Plant Extracts; D013343:Styrenes; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C030626:4-vinylphenol