Angiostatic activity of obtustatin as alpha1beta1 integrin inhibitor in experimental melanoma growth.
The presented results show the effect of targeting of collagen receptor, alpha1beta1 integrin expressed on the endothelial cells on the development of experimental melanoma and pathological angiogenesis. Obtustatin, a snake venom KTS-disintegrin, was applied as a specific inhibitor of this integrin. This low molecular weight peptide revealed a potent therapeutic effect on melanoma progression in 2 animal systems, mouse and quail. Its oncostatic effect was related to the inhibition of angiogenesis. Obtustatin inhibited the neovascularization ratio on the CAM embryo of quail, which was pathologically induced by the developing tumor. The i.v. administration of obtustatin completely blocked cancer growth of MV3 human melanoma in nude mice. In B16F10 syngeneic mouse model treatment with the disintegrin revealed a lower effect, although the development of the tumor was significantly reduced for both dosages. The mechanism of obtustatin action is related to the blocking of microvascular endothelial cell proliferation, which undergoes apoptosis in caspase-dependent manner. Summarizing, we present studies of low molecular weight disintegrin, obtustatin as a potential therapeutic compound for treatment of melanoma that contain a high level of vascularization.
Brown
Meghan C
MC
Department of Neuroscience, Center for Neurovirology and Cancer Biology, Temple University, School of Medicine, Philadelphia, PA, USA.
Staniszewska
Izabela
I
Del Valle
Luis
L
Tuszynski
George P
GP
Marcinkiewicz
Cezary
C
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049033:Chorioallantoic Membrane / Q000187:drug effects; D003370:Coturnix; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D039222:Integrin alpha1beta1 / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D039222:Integrin alpha1beta1; D014757:Viper Venoms; C474313:obtustatin, Vipera lebetina obtusa