Philinopside E, a new sulfated saponin from sea cucumber, blocks the interaction between kinase insert domain-containing receptor (KDR) and alphavbeta3 integrin via binding to the extracellular domain of KDR.
Vascular endothelial growth factor (VEGF) 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 kinase insert domain-containing receptor (KDR) is important in regulating angiogenesis and tumor development. We have reported previously that a new marine-derived compound, philinopside E (PE), exhibited the antiangiogenic 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-molecule 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 of 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.
Tian
Fang
F
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
Zhu
Cai-hua
CH
Zhang
Xiong-wen
XW
Xie
Xin
X
Xin
Xian-liang
XL
Yi
Yang-hua
YH
Lin
Li-ping
LP
Geng
Mei-yu
MY
Ding
Jian
J
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006027:Glycosides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D012503:Saponins / Q000737:chemistry*; D012616:Sea Cucumbers / Q000737:chemistry*; D013463:Sulfuric Acid Esters / Q000737:chemistry*; D014315:Triterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D006027:Glycosides; D039302:Integrin alphaVbeta3; C512676:Philinopside E; D012503:Saponins; D013463:Sulfuric Acid Esters; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2