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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Cell Adhesion / drug effects
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cyclin B1 / metabolism
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Cyclin D1 / metabolism
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Down-Regulation
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Drugs, Chinese Herbal / pharmacology
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Extracellular Matrix Proteins / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Hedyotis / metabolism
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Human Umbilical Vein Endothelial Cells / drug effects
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Humans
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MAP Kinase Signaling System / drug effects
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Male
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Matrix Metalloproteinase 2 / biosynthesis
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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NF-kappa B / biosynthesis
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Neovascularization, Pathologic / drug therapy*
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Phenols / pharmacology*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation / drug effects
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Plant Extracts / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism*
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Styrenes / metabolism
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Vascular Endothelial Growth Factor Receptor-1 / biosynthesis
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Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
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Zebrafish
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Angiogenesis Inhibitors
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CCNB1 protein, human
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CCND1 protein, human
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Cyclin B1
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Drugs, Chinese Herbal
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Extracellular Matrix Proteins
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NF-kappa B
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Phenols
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Plant Extracts
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Styrenes
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Cyclin D1
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Phosphatidylinositol 3-Kinases
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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MMP2 protein, human
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Matrix Metalloproteinase 2
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4-vinylphenol