Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway
Abstract
// Ning Tang 1, * , Lei Shi 2, * , Zhenlong Yu 1, 4, * , Peipei Dong 1 , Chao Wang 1 , Xiaokui Huo 1 , Baojing Zhang 1 , Shanshan Huang 1 , Sa Deng 1 , Kexin Liu 1 , Tonghui Ma 3 , Xiaobo Wang 4 , Lijun Wu 4 , Xiao-Chi Ma 1, 4 1 College of Pharmacy, Academy of Integrative Medicine, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China 2 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China 3 College of Basic Medical Science, Dalian Medical University, Dalian, China 4 Department of Pharmacy and Traditional Chinese medicine, Chinese People’s Liberation Army 210 Hospital, Dalian, China * These authors have contributed equally to this work Correspondence to: Xiao-Chi Ma, e-mail: [email protected] Keywords: gamabufotalin, angiogenesis, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), aortic ring Received: August 18, 2015 Accepted: November 21, 2015 Published: December 09, 2015 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.