title: Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway.
abstract: Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luan
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Yun-Ge
authors.initials: YG
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Ying-Yun
authors.initials: YY
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Pharmacy, Shanghai Institute of Health Sciences and Health School Attached to SJTU-SM, 279 Zhouzhu Road, Shanghai 201318, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Ya-Rong
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. Electronic address: fangchao100@hotmail.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. Electronic address: hongzhuan_chen@hotmail.com.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D029422:Campanulaceae; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012503:Saponins / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects* / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D012503:Saponins; D014315:Triterpenes; C108953:platycodin D; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Antiangiogenic cancer therapy; Chick embryo chorioallantoic membrane; Platycodin D; Triterpenoid; Tumor angiogenesis; VEGFR2