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First published on June 12, 2007; DOI: 10.1124/mol.107.036350

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Received for publication March 28, 2007.
Revised June 11, 2007.
Accepted for publication June 12, 2007.

Philinopside E, a New Sulfated Saponin from Sea Cucumber, Blocks the Interaction between KDR and {alpha}v{beta}3 Integrin via Binding to the Extracellular Domain of KDR

Fang Tian 1, Cai-hua Zhu 1, Xiong-wen Zhang 1, Xin Xie 1, Xian-liang Xin 2, Yang-hua Yi 3, Li-ping Lin 1, Mei-yu Geng 2, Jian Ding 1*

1 Shanghai Institute of Materia Medica 2 Marine Drug and Food Institute, Ocean University of China 3 Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University

* Address correspondence to: E-mail: jding{at}mail.shcnc.ac.cn

Abstract

Vascular endothelial growth factor signaling pathway is essential for tumor angiogenesis and has long been recognized as a promising target for cancer therapy. Current view holds that physical interaction between {alpha}v{beta}3 integrin and KDR is important in regulating angiogenesis and tumor development. We have previously reported that a new marine-derived compound, philinopside E (PE), exhibited the anti-angiogenic activity via inhibition on KDR phosphorylation and downstream signaling. Herein, we have further demonstrated that PE specifically interacts with KDR extracellular domain, which is distinct from conventional small molecular inhibitors targeting cytoplasmic kinase domain, to block its interaction with VEGF and the downstream signaling. We also noted that PE markedly suppresses {alpha}v{beta}3 integrin-driven downstream signaling as a result of disturbance of the physical interaction between KDR and {alpha}v{beta}3 integrin in HMECs, followed by disruption of the actin cytoskeleton organization and decreased cell adhesion to vitronectin. All these findings substantiate PE to be an unrecognized therapeutic class in tumor angiogenesis and more importantly, help appeal the interest of the therapeutic potential in angiogenesis and cancer development via targeting integrin-KDR interaction in the future.


Key words: Membrane targets, Angiogenesis


This article has been cited by other articles:


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G. Serini, L. Napione, M. Arese, and F. Bussolino
Besides adhesion: new perspectives of integrin functions in angiogenesis
Cardiovasc Res, May 1, 2008; 78(2): 213 - 222.
[Abstract] [Full Text] [PDF]


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