Accutin, a new disintegrin, inhibits angiogenesis in vitro and in vivo by acting as integrin alphavbeta3 antagonist and inducing apoptosis.
Endothelial integrins play an essential role in angiogenesis and cell survival. Accutin, a new member of disintegrin family derived from venom of Agkistrodon acutus, potently inhibited human platelet aggregation caused by various agonists (eg, thrombin, collagen, and, adenosine diphosphate [ADP]) through the blockade of fibrinogen binding to platelet glycoprotein IIb/IIIa (ie, integrin alphaIIbbeta3). In this report, we describe that accutin specifically inhibited the binding of monoclonal antibody (MoAb) 7E3, which recognizes integrin alphavbeta3, to human umbilical vein endothelial cells (HUVECs), but not those of other anti-integrin MoAbs such as alpha2beta1, alpha3beta1, and alpha5beta1. Moreover, accutin, but not the control peptide GRGES, dose-dependently inhibited the 7E3 interaction with HUVECs. Both 7E3 and GRGDS, but not GRGES or Integrelin, significantly blocked fluorescein isothiocyanate-conjugated accutin binding to HUVEC. In functional studies, accutin exhibited inhibitory effects on HUVEC adhesion to immobilized fibrinogen, fibronectin and vitronectin, and the capillary-like tube formation on Matrigel in a dose- and RGD-dependent manner. In addition, it exhibited an effective antiangiogenic effect in vivo when assayed by using the 10-day-old embryo chick CAM model. Furthermore, it potently induced HUVEC apoptotic DNA fragmentation as examined by electrophoretic and flow cytometric assays. In conclusion, accutin inhibits angiogenesis in vivo and in vitro by blocking integrin alphavbeta3 of endothelial cells and by inducing apoptosis. The antiangiogenic activity of disintegrins might be explored as the target of developing the potential antimetastatic agents.
Yeh
C H
CH
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Peng
H C
HC
Huang
T F
TF
D000077284:Abciximab; D017836:Agkistrodon / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002642:Chick Embryo; D003435:Crotalid Venoms / Q000737:chemistry / Q000494:pharmacology*; D053938:DNA Fragmentation; D003864:Depression, Chemical; D019483:Disintegrins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D000077542:Eptifibatide; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D014471:Umbilical Veins
D000911:Antibodies, Monoclonal; D003435:Crotalid Venoms; D019483:Disintegrins; D007140:Immunoglobulin Fab Fragments; D009842:Oligopeptides; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; C115498:accutin; C092614:glycyl-arginyl-glycyl-glutamyl-serine; D005340:Fibrinogen; C049554:glycyl-arginyl-glycyl-aspartyl-serine; D000077542:Eptifibatide; D000077284:Abciximab