Alphastatin-C a new inhibitor of endothelial cell activation is a pro-arteriogenic agent in vivo and retards B16-F10 melanoma growth in a preclinical model
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Adilson Kleber Ferreira2,3, Brunella Cristofaro8, Milene Cristina Menezes1, Ana Karina de Oliveira1, Alexandre Keiji Tashima1,9, Robson Lopes de Melo1, Cristiane Castilho Fernandes Silva4, Miryam Guillermina Palomino Rodriguez1, Daniela Cajado de Oliveira Souza Carvalho4, Ricardo Alexandre de Azevedo10, Paulo Luiz de Sá Junior7, Lisley Inata Mambelli2, Fernanda Vieira Portaro4, Luc Pardanaud5,6, Anne Eichmann5,6, Osvaldo Augusto Sant’Anna1 and Mxarcella Faria1
1 Special Laboratory of Applied Toxinology, Center of Toxins, Immune-Response and Cell Signaling (CeTICS), Butantan Institute, São Paulo, SP, Brazil
2 Department of Immunology, Laboratory of Tumor Immunology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil
3 Alchemypet, Veterinary Dignostic Medicine, CIETEC/IPEN, Department of Oncology, University of Sao Paulo, Sao Paulo, Brazil
4 Immunochemistry Laboratory, Butantan Institute, São Paulo, SP, Brazil
5 Cardiovascular Research Center and the Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
6 INSERM U970, Paris Cardiovascular Research Center, Paris, France
7 Mogi das Cruzes University (UMC), Villa Lobos Campus, Sao Paulo, SP, Brazil
8 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France
9 Department of Biochemistry, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, Brazil
10 Experimental Oncology Unit (UNONEX), Federal University of Sao Paulo, Sao Paulo, SP, Brazil
|Marcella Faria,||email:||[email protected]|
|Adilson Kleber Ferreira,||email:||[email protected]|
Keywords: alphastatin-C; angiogenesis; peptides; melanoma; angiostatic
Received: December 22, 2017 Accepted: June 23, 2018 Published: December 22, 2020
Most characterized angiogenic modulators are proteolytic fragments of structural plasma and/or matrix components. Herein, we have identified a novel anti-angiogenic peptide generated by the in vitro hydrolysis of the C-terminal moiety of the fibrinogen alpha chain, produced by the snake venom metalloprotease bothropasin (SVMP), a hemorrhagic proteinase in Bothrops jararaca venom. The 14-amino acids peptide (alphastatin-C) is a potent antagonist of basic fibroblast growth factor, induced endothelial cell (HUVEC-CS) proliferation, migration and capillary tube formation in matrigel. It also inhibits cell adhesion to fibronectin. The basis of the antagonism between bFGF and alphastatin-C is elucidated by the inhibition of various bFGF induced signaling pathways and their molecular components modification, whenever the combination of the stimuli is provided, in comparison to the treatment with bFGF only. To corroborate to the potential therapeutic use of alphastatin-C, we have chosen to perform in vivo assays in two distinct angiogenic settings. In chick model, alphastatin-C inhibits chorioallantoic membrane angiogenesis. In mouse, it efficiently reduces tumor number and volume in a melanoma model, due to the impairment of tumor neovascularization in treated mice. In contrast, we show that the alphastatin-C peptide induces arteriogenesis, increasing pial collateral density in neonate mice. alphastatin-C is an efficient new antiangiogenic FGF-associated agent in vitro, it is an inhibitor of embryonic and tumor vascularization in vivo while, it is an arteriogenic agent. The results also suggest that SVMPs can be used as in vitro biochemical tools to process plasma and/or matrix macromolecular components unraveling new angiostatic peptides.
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