title: Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor-2.
abstract: OBJECTIVE
  Angiogenesis-based therapy is an effective anti-tumour strategy and previous reports have shown some beneficial effects of a naturally occurring bioactive compound plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). Here, we sought to determine the biological effects of plumbagin on signalling mechanisms during tumour angiogenesis.
  
  
  METHODS
  The effects of plumbagin were evaluated in various in vitro assays which utilised human umbilical vein endothelial cells (HUVEC) proliferation, migration and tube formation. Plumbagin was also evaluated in vivo using chicken embryo chorioallantoic membrane (CAM) and mouse corneal micropocket models., Human colon carcinoma and prostate cancer xenograft mouse models were used to evaluate the effects of plumbagin on angiogenesis. Immunofluorescence, GST pull-down and Western blotting were employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated Ras signalling pathways.
  
  
  RESULTS
  Plumbagin not only inhibited endothelial cell proliferation, migration and tube formation but also suppressed chicken chorioallantoic membrane neovascularzation and VEGF-induced mouse corneal angiogenesis. Moreover, plumbagin suppressed tumour angiogenesis and tumour growth in human colon carcinoma and prostate cancer xenograft mouse models. At a molecular level, plumbagin blocked the Ras/Rac/cofilin and Ras/MEK signalling pathways mediated by VEGFR2 in HUVECs.
  
  
  CONCLUSIONS
  Plumbagin inhibited tumour angiogenesis and tumour growth by interference with the VEGFR2-mediated Ras signalling pathway in endothelial cells. Our findings demonstrate a molecular basis for the effects of plumbagin and suggest that this compound might have therapeutic ant-tumour effects.
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lai
authors.forename: Junchen
authors.initials: J
authors.lastname: Liu
authors.forename: Dong
authors.initials: D
authors.lastname: Zhai
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Lin
authors.forename: Lijun
authors.initials: L
authors.lastname: He
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Dong
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Binbin
authors.initials: B
authors.lastname: Lu
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D009285:Naphthoquinones; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D018631:ras Proteins; C014758:plumbagin