title: Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis.
abstract: Anti-angiogenesis targeting VEGFR2 has been an attractive strategy for cancer therapy for its role in promoting cancer growth and metastasis. However, the currently available drugs have unexpected side effects. Therefore, development of novel VEGFR2 inhibitors with less toxicity would be of great value. In this study, we describe a novel and safely VEGFR2 inhibitor, Salinomycin (Sal), which was screened from the drug libraries of Food and Drug Administration (FDA) and prohibited the binding of the ATP at its binding pocket of VEGFR2 using molecular docking model. Sal could interfere a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation in HUVECS in vitro. Matrigel plug model demonstrated Sal strongly inhibited angiogenesis in vivo. We found that Sal significantly decreased VEGF-induced phosphorylation of VEGFR2 and its downstream STAT3 in dose- and time-dependent manner in HUVECs. Besides, Sal could directly reduce the cell viability and induce apoptosis in SGC-7901 cancer cells in vitro. Sal inhibited constitutive STAT3 activation by blocking its DNA binding and reduced various gene products including Bcl-2, Bcl-xL and VEGF both at mRNA and protein levels. Intra-peritoneal injection of Sal at doses of 3 and 5 mg/kg/day markedly suppressed human gastric cancer xenografts angiogenesis and growth without causing obvious toxicities. Taken together, Sal inhibits tumor angiogenesis and growth of gastric cancer; our results reveal unique characteristics of Sal as a promising anticancer drug candidate.
authors.affiliation: Department of Oncology, General Hospital of the Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.|Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.|Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.|Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.|Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Huo
authors.affiliation: Department of Oncology, General Hospital of the Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Qilun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.|Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China.|Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011714:Pyrans; D040301:Vascular Endothelial Growth Factor Receptor-2; C010327:salinomycin; D000095662:Polyether Polyketides; C000588866:KDR protein, human
keywords: angiogenesis; gastric cancer; salinomycin; tumor growth; vascular endothelial growth factor 2