title: Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway.
abstract: Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Tang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.|Department of Pharmacy and Traditional Chinese medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Dong
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Baojing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Sa
authors.initials: S
authors.lastname: Deng
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: College of Basic Medical Science, Dalian Medical University, Dalian, China.
authors.forename: Tonghui
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Pharmacy and Traditional Chinese medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacy and Traditional Chinese medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.|Department of Pharmacy and Traditional Chinese medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Xiao-Chi
authors.initials: XC
authors.lastname: Ma
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002018:Bufanolides / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: D020533:Angiogenesis Inhibitors; D002018:Bufanolides; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000612263:gamabufotalin; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: angiogenesis; aortic ring; gamabufotalin; vascular endothelial growth factor (VEGF); vascular endothelial growth factor receptor 2 (VEGFR-2)