{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:28:43Z","timestamp":1789576123872,"version":"build-2803163510"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2012\/51241\u20135"],"award-info":[{"award-number":["2012\/51241\u20135"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Antitumor property of Crotoxin (CTX), the major toxin from <jats:italic>Crotalus durissus terrificus<\/jats:italic> snake venom, has been demonstrated in experimental animal models and clinical trials. However, the direct action of this toxin on the significant events involved in neovascularization, which are essential for tumor growth and survival, has not been confirmed. This study investigated the effects of CTX on the key parameters of neovascularization in two- and three-dimensional culture models. Murine endothelial cell lines derived from thymus hemangioma (t.End.1) were treated at different concentrations of CTX (6.25\u2013200\u00a0nM). Endothelial cell proliferation, cell adhesion, and actin cytoskeletal dynamics on laminin (10\u00a0\u00b5g\/ml), type I collagen (10\u00a0\u00b5g\/ml), and fibronectin (3\u00a0\u00b5g\/ml) were evaluated along with the endothelial cell migration and formation of capillary-like tubes in 3D Matrigel. CTX concentration of 50\u00a0nM inhibited tube formation on 3D Matrigel and impaired cell adhesion, proliferation, and migration under both culture medium and tumor-conditioned medium. These actions were not accountable for the loss of cell viability. Inhibition of cell adhesion to different extracellular matrix components was related to the reduction of \u03b1v and \u03b12 integrin distribution and cytoskeletal actin polymerization (F-actin), accompanied by inhibition of focal adhesion kinase (FAK), Rac1 (GTPase) signaling proteins, and actin-related protein 2\/3 (Arp 2\/3) complex. This study proved that CTX inhibits the major events involved in angiogenesis, particularly against tumor stimuli, highlighting the importance of the anti-angiogenic action of CTX in inhibition of tumor progression.<\/jats:p>","DOI":"10.3389\/fphar.2021.713332","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T05:06:22Z","timestamp":1628053582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Crotoxin Inhibits Endothelial Cell Functions in Two- and Three-dimensional Tumor Microenvironment"],"prefix":"10.3389","volume":"12","author":[{"given":"Ellen Emi","family":"Kato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Ara\u00fajo","family":"Pimenta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u00edra Estanislau Soares de","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Olzon","family":"Zambelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinilce Fagundes dos","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Coccuzzo","family":"Sampaio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.toxicon.2013.01.001","article-title":"Identification of \u03b12\u03b21 Integrin Inhibitor VP-I with Anti-Platelet Properties in the Venom of Vipera Palaestinae","volume":"64","author":"Arlinghaus","year":"2013","journal-title":"Toxicon."},{"key":"B2","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/s10456\u2013009\u20139146\u2013410.1007\/s10456-009-9146-4","article-title":"The Endothelial Cell Tube Formation Assay on Basement Membrane Turns 20: State of the Science and the Art","volume":"12","author":"Arnaoutova","year":"2009","journal-title":"Angiogenesis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1038\/nprot.2010.6","article-title":"In Vitro Angiogenesis: Endothelial Cell Tube Formation on Gelled Basement Membrane Extract","volume":"5","author":"Arnaoutova","year":"2010","journal-title":"Nat. Protoc."},{"key":"B4","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1002\/path.1571","article-title":"Haemangiomas Are Formed by Cells Expressing High Levels Of \u03b1v\u03b23 Integrin and Lacking Acetylated LDL Uptake","volume":"203","author":"Aurrand-Lions","year":"2004","journal-title":"J. Pathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1038\/nrc2353","article-title":"Integrins in Angiogenesis and Lymphangiogenesis","volume":"8","author":"Avraamides","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/s00441-009-0834-6","article-title":"Integrins","volume":"339","author":"Barczyk","year":"2010","journal-title":"Cell Tissue Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e10124","DOI":"10.1371\/journal.pone.0010124","article-title":"MVL-PLA2, A Snake Venom Phospholipase A2, Inhibits Angiogenesis Through an Increase in Microtubule Dynamics and Disorganization of Focal Adhesions","volume":"5","author":"Bazaa","year":"2010","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.3390\/ijms17122037","article-title":"Integrins in the Spotlight of Cancer","volume":"17","author":"Bianconi","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1152\/physiolgenomics.00170.2013","article-title":"Influence of the Microenvironment on Cell Fate Determination and Migration","volume":"46","author":"Bloom","year":"2014","journal-title":"Physiol. Genomics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/37126","article-title":"Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance","volume":"390","author":"Boehm","year":"1997","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/2457532","article-title":"Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4","volume":"2016","author":"Brigatte","year":"2016","journal-title":"Mediators Inflamm."},{"key":"B12","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/s0092-8674(00)81235-0","article-title":"Localization of Matrix Metalloproteinase MMP-2 to the Surface of Invasive Cells by Interaction with Integrin \u03b1v\u03b23","volume":"85","author":"Brooks","year":"1996","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1007\/s00018-007-7008-z","article-title":"What Tangled Webs They Weave: Rho-GTPase Control of Angiogenesis","volume":"64","author":"Bryan","year":"2007","journal-title":"Cell. Mol. Life Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.yexcr.2015.10.029","article-title":"Focal Adhesions, Stress Fibers and Mechanical Tension","volume":"343","author":"Burridge","year":"2016","journal-title":"Exp. Cel. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2122","DOI":"10.1016\/0192-0561(91)90283-d","article-title":"Murine Endothelioma Cell Lines Transformed by Polyoma Middle T Oncogene as Target for and Producers of Cytokines","volume":"147","author":"Bussolino","year":"1991","journal-title":"J. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.2174\/1568026619666181221120817","article-title":"Animal Venoms Have Potential to Treat Cancer","volume":"18","author":"Chatterjee","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.toxicon.2013.08.057","article-title":"Involvement of Formyl Peptide Receptors in the Stimulatory Effect of Crotoxin on Macrophages Co-cultivated with Tumour Cells","volume":"74","author":"Costa","year":"2013","journal-title":"Toxicon."},{"key":"B18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3109\/08923979809034806","article-title":"Tumor Regression of Advanced Carcinomas Following Intra-and\/or Peri-Tumoral Inoculation with VRCTC-310 in Humans: Preliminary Report of Two Cases","volume":"20","author":"Costa","year":"1998","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"B19","first-page":"1033","article-title":"Phase I and Pharmacokinetics Study of Crotoxin (Cytotoxic PLA(2), NSC-624244) in Patients with Advanced Cancer","volume":"8","author":"Cura","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1177\/154405910708601005","article-title":"Angiogenesis Inhibitors and the Need for Anti-Angiogenic Therapeutics","volume":"86","author":"Dass","year":"2007","journal-title":"J. Dent Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1161\/01.RES.0000191547.64391.e3","article-title":"Endothelial Extracellular Matrix","volume":"97","author":"Davis","year":"2005","journal-title":"Circ. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1016\/0041-0101(87)90136-x","article-title":"Determination of Phospholipase A2 Activity by a Colorimetric Assay Using a pH Indicator","volume":"25","author":"de Ara\u00fajo","year":"1987","journal-title":"Toxicon."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4281","DOI":"10.1038\/s41598-019-40903-0","article-title":"Crotoxin Promotes Macrophage Reprogramming Toward an Anti-Angiogenic Phenotype","volume":"9","author":"de Ara\u00fajo Pimenta","year":"2019","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1083\/jcb.200208050","article-title":"Cell Migration Requires Both Ion Translocation and Cytoskeletal Anchoring by the Na-H Exchanger NHE1","volume":"159","author":"Denker","year":"2002","journal-title":"J. Cel. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1016\/0006-2952(96)00097-4","article-title":"Regulation of Epidermal Growth Factor Receptor Activity by Crotoxin, A Snake Venom Phospholipase A2 Toxin","volume":"51","author":"Donato","year":"1996","journal-title":"Biochem. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.mvr.2008.12.003","article-title":"Inhibition of Angiogenesis In Vitro: A central Role for \u03b2-actin Dependent Cytoskeletal Remodeling","volume":"77","author":"Durham","year":"2009","journal-title":"Microvasc. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1007\/bf03401768","article-title":"The Role of \u03b1v Integrins During Angiogenesis","volume":"4","author":"Eliceiri","year":"1998","journal-title":"Mol. Med."},{"key":"B29","article-title":"Lipoxin A4 Contributes to Inhibitory Effect of Crotoxin on Growth of Walker 256 Tumor","author":"Faiad","year":"2008"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.11606\/D.42.2012.tde-18042013-085640","volume-title":"Efeito da Crotoxina sobre fun\u00e7\u00e3o e o metabolismo de glicose e glutamina de macr\u00f3fagos durante a progress\u00e3o tumoral","author":"Faiad","year":"2012"},{"key":"B31","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1021\/bi00402a036","article-title":"Crotoxin, a Phospholipase A2 Neurotoxin from the South American Rattlesnake Crotalus durissus Terrificus: Purification of Several Isoforms and Comparison of Their Molecular Structure and of Their Biological Activities","volume":"27","author":"Faure","year":"1988","journal-title":"Biochemistry"},{"key":"B32","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.plefa.2005.05.016","article-title":"Angiogenesis and Lipoxins","volume":"73","author":"Fierro","year":"2005","journal-title":"Prostaglandins, Leukot. Essent. Fatty Acids"},{"key":"B33","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/nm0195-27","article-title":"Angiogenesis in Cancer, Vascular, Rheumatoid and Other Disease","volume":"1","author":"Folkman","year":"1995","journal-title":"Nat. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/288551a0","article-title":"Angiogenesis In Vitro","volume":"288","author":"Folkman","year":"1980","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1053\/sonc.2002.3726310.1016\/s0093-7754(02)70065-1","article-title":"Role of Angiogenesis in Tumor Growth and Metastasis","volume":"29","author":"Folkman","year":"2002","journal-title":"Semin. Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/0003\u20139861(56)90397\u2013610.1016\/0003-9861(56)90397-6","article-title":"Fractionation and Composition of Crotoxin","volume":"60","author":"Fraenkel-Conrat","year":"1956","journal-title":"Arch. Biochem. Biophys."},{"key":"B37","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/bjc.1995.149","article-title":"Endothelial Cell Differentiation into Capillary-like Structures in Response to Tumour Cell Conditioned Medium: A Modified Chemotaxis Chamber Assay","volume":"71","author":"Garrido","year":"1995","journal-title":"Br. J. Cancer"},{"key":"B38","volume-title":"Primer of Bio-Statistics","author":"Glantz","year":"1997"},{"key":"B39","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/bs.apha.2017.08.011","article-title":"Integrins in Vascular Development and Pathology","volume":"81","author":"Guerrero","year":"2018","journal-title":"Adv. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3389\/fbioe.2015.00062","article-title":"Matrix-Immobilized BMP-2 on Microcontact Printed Fibronectin as an In Vitro Tool to Study BMP-Mediated Signaling and Cell Migration","volume":"3","author":"Hauff","year":"2015","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"362","DOI":"10.3390\/cells8040362","article-title":"The Cytoskeleton-A Complex Interacting Meshwork","volume":"8","author":"Hohmann","year":"2019","journal-title":"Cells"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1126\/science.1070200","article-title":"Tumor Regression by Targeted Gene Delivery to the Neovasculature","volume":"296","author":"Hood","year":"2002","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nrc727","article-title":"Role of Integrins in Cell Invasion and Migration","volume":"2","author":"Hood","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"B44","first-page":"1191","article-title":"Inhibition of Endothelial Cell Function In Vitro and Angiogenesis In Vivo by Docetaxel (Taxotere): Association with Impaired Repositioning of the Microtubule Organizing center","volume":"1","author":"Hotchkiss","year":"2002","journal-title":"Mol. Cancer Ther."},{"key":"B45","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1006\/bbrc.2000.3130","article-title":"Suppressive Mechanism of Salmosin, A Novel Disintegrin in B16 Melanoma Cell Metastasis","volume":"275","author":"Kang","year":"2000","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"4249","DOI":"10.1091\/mbc.e08-05-0501","article-title":"Epidermal Growth Factor-Induced Enhancement of Glioblastoma Cell Migration in 3D Arises from an Intrinsic Increase in Speed but an Extrinsic Matrix- and Proteolysis-dependent Increase in Persistence","volume":"19","author":"Kim","year":"2008","journal-title":"Mol. Biol. Cel."},{"key":"B47","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1161\/01.RES.0000259593.07661.1e","article-title":"Endothelial Cell Migration During Angiogenesis","volume":"100","author":"Lamalice","year":"2007","journal-title":"Circ. Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1083\/jcb.109.5.2455","article-title":"Endothelial Cells Use Alpha 2 Beta 1 Integrin as a Laminin Receptor","volume":"109","author":"Languino","year":"1989","journal-title":"J. Cel. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1258\/ebm.2012.012010","article-title":"Crotoxin, A Rattlesnake Toxin, Induces A Long-Lasting Inhibitory Effect on Phagocytosis by Neutrophils","volume":"237","author":"Lima","year":"2012","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.1016\/j.biocel.2013.06.009","article-title":"Applications of Snake Venom Components to Modulate Integrin Activities in Cell-Matrix Interactions","volume":"45","author":"Marcinkiewicz","year":"2013","journal-title":"Int. J. Biochem. Cel. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"jcs239434","DOI":"10.1242\/jcs.239434","article-title":"\u03b1v\u03b28 Integrin Adhesion and Signaling Pathways in Development, Physiology and Disease","volume":"133","author":"McCarty","year":"2020","journal-title":"J. Cel. Sci."},{"key":"B53","doi-asserted-by":"crossref","DOI":"10.1016\/j.toxicon.2019.06.106","volume-title":"Crotoxin Modulates the Phenotypic Reprogramming of Quiescent Macrophages or Stimulated by Tumor Microenvironment","author":"Neves","year":"2019"},{"key":"B54","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/bf00874149","article-title":"VRCTC-310 ? A Novel Compound of Purified Animal Toxins Separates Antitumor Efficacy from Neurotoxicity","volume":"11","author":"Newman","year":"1993","journal-title":"Invest. New Drugs"},{"key":"B55","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.matbio.2005.12.001","article-title":"Ligand-binding Specificities of Laminin-Binding Integrins: A Comprehensive Survey of Laminin-Integrin Interactions Using Recombinant \u03b13\u03b21, \u03b16\u03b21, \u03b17\u03b21 and \u03b16\u03b24 Integrins","volume":"25","author":"Nishiuchi","year":"2006","journal-title":"Matrix Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.toxicon.2009.12.011","article-title":"Crotoxin Is Responsible for the Long-Lasting Anti-inflammatory Effect of Crotalus durissus Terrificus Snake Venom: Involvement of Formyl Peptide Receptors","volume":"55","author":"Nunes","year":"2010","journal-title":"Toxicon."},{"key":"B57","doi-asserted-by":"publisher","first-page":"9346","DOI":"10.1021\/bi027212o","article-title":"New Lytic Peptides Based on Thed,l-Amphipathic Helix Motif Preferentially Kill Tumor Cells Compared to Normal Cells\u2020","volume":"42","author":"Papo","year":"2003","journal-title":"Biochemistry"},{"key":"B58","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/s0092-8674(03)00120-x","article-title":"Cellular Motility Driven by Assembly and Disassembly of Actin Filaments","volume":"112","author":"Pollard","year":"2003","journal-title":"Cell"},{"key":"B59","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1146\/annurev.biophys.35.040405.101936","article-title":"Regulation of Actin Filament Assembly by Arp2\/3 Complex and Formins","volume":"36","author":"Pollard","year":"2007","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"B60","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1126\/science.1092053","article-title":"Cell Migration: Integrating Signals from Front to Back","volume":"302","author":"Ridley","year":"2003","journal-title":"Science"},{"key":"B61","doi-asserted-by":"publisher","first-page":"894","DOI":"10.2174\/092986609788923266","article-title":"Snake Venom Phospholipases A2: A New Class of Antitumor Agents","volume":"16","author":"Rodrigues","year":"2009","journal-title":"Protein Pept. Lett."},{"key":"B62","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.it.2004.02.006","article-title":"CXC Chemokines: The Regulatory Link Between Inflammation and Angiogenesis","volume":"25","author":"Romagnani","year":"2004","journal-title":"Trends Immunol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/bf00873958","article-title":"In Vitro Comparison of Cytotoxic Effects of Crotoxin Against Three Human Tumors and a Normal Human Epidermal Keratinocyte Cell Line","volume":"12","author":"Rudd","year":"1994","journal-title":"Invest. New Drugs"},{"key":"B64","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/s0041-0101(97)00097-4","article-title":"Purification and Characterization of Three Acidic, Cytotoxic Phospholipases A2 from Indian Cobra (Naja naja naja) Venom","volume":"36","author":"Rudrammaji","year":"1998","journal-title":"Toxicon."},{"key":"B65","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.toxicon.2005.11.008","article-title":"Lipoxygenase-Derived Eicosanoids Are Involved in the Inhibitory Effect of Crotalus durissus Terrificus Venom or Crotoxin on Rat Macrophage Phagocytosis","volume":"47","author":"Sampaio","year":"","journal-title":"Toxicon."},{"key":"B66","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/s0041-0101(03)00069-2","article-title":"Contribution of Crotoxin for the Inhibitory Effect of Crotalus durissus Terrificus Snake Venom on Macrophage Function","volume":"41","author":"Sampaio","year":"2003","journal-title":"Toxicon."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/j.toxicon.2010.01.011","article-title":"Crotoxin: Novel Activities for a Classic \u03b2-neurotoxin","volume":"55","author":"Sampaio","year":"2010","journal-title":"Toxicon."},{"key":"B68","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.toxicon.2006.03.004","article-title":"Crotoxin Induces Actin Reorganization and Inhibits Tyrosine Phosphorylation and Activity of Small GTPases in Rat Macrophages","volume":"47","author":"Sampaio","year":"","journal-title":"Toxicon."},{"key":"B69","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s40409-018-0178-3","article-title":"Immunotherapeutic Potential of Crotoxin: Anti-inflammatory and Immunosuppressive Properties","volume":"24","author":"Sartim","year":"2018","journal-title":"J. Venom Anim. Toxins Incl. Trop. Dis."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1016\/j.yexcr.2013.03.016","article-title":"The Selective Role of ECM Components on Cell Adhesion, Morphology, Proliferation and Communication In Vitro","volume":"319","author":"Schlie-Wolter","year":"2013","journal-title":"Exp. Cel. Res."},{"key":"B71","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.cellsig.2011.11.013","article-title":"Modulation of Chemotactic and Pro-inflammatory Activities of Endothelial Progenitor Cells by Hepatocellular Carcinoma","volume":"24","author":"Shih","year":"2012","journal-title":"Cell Signal."},{"key":"B72","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.cbpc.2005.11.020","article-title":"Bothrops Moojeni Myotoxin-II, a Lys49-Phospholipase A2 Homologue: An Example of Function Versatility of Snake Venom Proteins","volume":"142","author":"St\u00e1beli","year":"2006","journal-title":"Comp. Biochem. Physiol. C: Toxicol. Pharmacol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"e0201858","DOI":"10.1371\/journal.pone.0201858","article-title":"Proteasome Inhibition Induces IKK-Dependent Interleukin-8 Expression in Triple Negative Breast Cancer Cells: Opportunity for Combination Therapy","volume":"13","author":"Uddin","year":"2018","journal-title":"PLoS One"},{"key":"B74","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1161\/01.ATV.0000209518.58252.17","article-title":"Pericellular Proteases in Angiogenesis and Vasculogenesis","volume":"26","author":"van Hinsbergh","year":"2006","journal-title":"Atvb"},{"key":"B75","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.biopha.2017.02.071","article-title":"Angiomodulators in Cancer Therapy: New Perspectives","volume":"89","author":"Varinska","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B76","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s10456-017-9562-9","article-title":"Tumor Angiogenesis and Vascular Normalization: Alternative Therapeutic Targets","volume":"20","author":"Viallard","year":"2017","journal-title":"Angiogenesis"},{"key":"B77","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.mvr.2011.05.002","article-title":"Focal Adhesion Kinase Regulation of Neovascularization","volume":"83","author":"Wary","year":"2012","journal-title":"Microvasc. Res."},{"key":"B78","doi-asserted-by":"publisher","first-page":"a006478","DOI":"10.1101\/cshperspect.a006478","article-title":"v Integrins in Angiogenesis and Cancer","volume":"1","author":"Weis","year":"2011","journal-title":"Cold Spring Harbor Perspect. Med."},{"key":"B79","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/0092-8674(88)90536-3","article-title":"Embryonic Lethalities and Endothelial Tumors in Chimeric Mice Expressing Polyoma Virus Middle T Oncogene","volume":"52","author":"Williams","year":"1988","journal-title":"Cell"},{"key":"B80","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1159\/000092423","article-title":"C-terminal Heparin-Binding Peptide of Snake Venom VEGF Specifically Blocks VEGF-Stimulated Endothelial Cell Proliferation","volume":"34","author":"Yamazaki","year":"2005","journal-title":"Pathophysiol. Haemos. Thromb."},{"key":"B82","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1016\/j.toxicon.2009.01.003","article-title":"Two Purified and Characterized Phospholipases A2 from Cerastes Cerastes Venom, that Inhibit Cancerous Cell Adhesion and Migration","volume":"53","author":"Zouari-Kessentini","year":"2009","journal-title":"Toxicon."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.713332\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T05:06:30Z","timestamp":1628053590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.713332\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,4]]},"references-count":80,"alternative-id":["10.3389\/fphar.2021.713332"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.713332","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,4]]},"article-number":"713332"}}