Oroxyloside inhibits angiogenesis through suppressing internalization of VEGFR2/Flk‐1 in endothelial cells

• Published in: Journal of cellular physiology Vol. 233; no. 4; pp. 3454 - 3464
• Main Authors: Zhao, Kai, Li, Xiaorui, Lin, Binyan, Yang, Dawei, Zhou, Yuxin, Li, Zhiyu, Guo, Qinglong, Lu, Na
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-04-2018
• Subjects: AKT protein; Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Angiogenesis Inhibitors - pharmacology; Anticancer properties; Aorta; Biocompatibility; Blood vessels; Cadherins; Cancer; Cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; Chorioallantoic membrane; Chorioallantoic Membrane - metabolism; Deoxyribonucleic acid; DNA; Endothelial cells; Flavones - pharmacology; Flavonoids; Glucuronides - pharmacology; Human Umbilical Vein Endothelial Cells - drug effects; Humans; In vivo methods and tests; Internalization; MAP kinase; Metabolites; Metastases; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Physiologic - drug effects; NF-κB protein; Nuclear transport; oroxyloside; Proto-Oncogene Proteins c-akt - metabolism; Toxicity; Translocation; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular endothelial growth factor receptor 2; Vascular Endothelial Growth Factor Receptor-2 - drug effects; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2; Xenografts; VEGFR2; oroxyloside; internalization; angiogenesis
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26198

Increasing flavonoids have been reported to possess anti‐angiogenic effects. Inhibition of angiogenesis plays a critical role in the treatment of cancer, especially in advanced metastatic cancer. In this study, we assessed the effect of Oroxylin A‐7‐glucuronide (Oroxyloside), a main metabolite of Oroxylin A, on angiogenesis in human endothelial cell‐like EA.hy926 cells. Oroxyloside suppressed the migration and tube formation of EA.hy926 cells. Meanwhile, microvessels sprouting from aortic rings and new blood vessels on the chicken chorioallantoic membrane (CAM) were also inhibited. Mechanism studies showed that Oroxyloside reduced the autophosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2/Flk‐1) while it up‐regulated the expression of R‐Ras and VE‐cadherin. In consequence, Oroxyloside inhibited the downstream Akt/MAPK/NF‐κB pathways and then decreased the nuclear translocation and DNA binding ability of NF‐κB. Furthermore, in vivo study showed that Oroxyloside exhibited a potential anti‐angiogenic effect in Matrigel plug assay and inhibited growth of xenografted tumors with low systemic toxicity, which could be ascribed to the inhibition of VEGFR2 internalization. Taken together, these results suggested that Oroxyloside could inhibit angiogenesis in vitro and in vivo via suppressing the internalization of VEGFR2 and might serve as a potential antitumor agent.
Oroxyloside can inhibit angiogenesis and promote vascular normalization in vivo and vitro. It is mainly ascribed to the internalization of VEGFR2 through up‐regulating the expression of R‐Ras and VE‐cadherin.