Oncotarget

Research Papers:

Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis

Tao Li, Xiaoxia Liu, Qin Shen, Wenjun Yang, Zhenghao Huo, Qilun Liu, Haiyan Jiao and Jing Chen _

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Oncotarget. 2016; 7:26580-26592. https://doi.org/10.18632/oncotarget.8555

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Abstract

Tao Li1,*, Xiaoxia Liu2,3,*, Qin Shen2,3, Wenjun Yang2,3, Zhenghao Huo2,3, Qilun Liu1, Haiyan Jiao2,3, Jing Chen2,3

1Department of Oncology, General Hospital of the Ningxia Medical University, Yinchuan 750004, China

2Department of Medical Genetic and Cell Biology, Ningxia Medical University, Yinchuan 750004, China

3Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China

*These authors contributed equally to this work

Correspondence to:

Jing Chen, email: [email protected]

Haiyan Jiao, email: [email protected]

Keywords: gastric cancer, salinomycin, angiogenesis, tumor growth, vascular endothelial growth factor 2

Received: August 05, 2015     Accepted: March 12, 2016     Published: April 02, 2016

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.


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