title: CR-LAAO, an L-amino acid oxidase from Calloselasma rhodostoma venom, as a potential tool for developing novel immunotherapeutic strategies against cancer.
abstract: L-amino acid oxidases from snake venoms have been described to possess various biological functions. In this study, we investigated the inflammatory responses induced in vivo and in vitro by CR-LAAO, an L-amino acid oxidase isolated from Calloselasma rhodostoma venom, and its antitumor potential. CR-LAAO induced acute inflammatory responses in vivo, with recruitment of neutrophils and release of IL-6, IL-1β, LTB4and PGE2. In vitro, IL-6 and IL-1β production by peritoneal macrophages stimulated with CR-LAAO was dependent of the activation of the Toll-like receptors TLR2 and TLR4. In addition, CR-LAAO promoted apoptosis of HL-60 and HepG2 tumor cells mediated by the release of hydrogen peroxide and activation of immune cells, resulting in oxidative stress and production of IL-6 and IL-1β that triggered a series of events, such as activation of caspase 8, 9 and 3, and the expression of the pro-apoptotic gene BAX. We also observed that CR-LAAO modulated the cell cycle of these tumor cells, promoting delay in the G0/G1 and S phases. Taken together, our results suggest that CR-LAAO could serve as a potential tool for the development of novel immunotherapeutic strategies against cancer, since this toxin promoted apoptosis of tumor cells and also activated immune cells against them.
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Tássia R
authors.initials: TR
authors.lastname: Costa
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Danilo L
authors.initials: DL
authors.lastname: Menaldo
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Karina F
authors.initials: KF
authors.lastname: Zoccal
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Burin
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Alexandre F
authors.initials: AF
authors.lastname: Aissa
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Fabíola A de
authors.initials: FA
authors.lastname: Castro
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Lúcia H
authors.initials: LH
authors.lastname: Faccioli
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Lusânia M
authors.initials: LM
authors.lastname: Greggi Antunes
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
authors.forename: Suely V
authors.initials: SV
authors.lastname: Sampaio
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D018836:Inflammation Mediators / Q000378:metabolism; D050830:L-Amino Acid Oxidase / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012910:Snake Venoms / Q000201:enzymology* / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D017819:Viperidae / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012910:Snake Venoms; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D050830:L-Amino Acid Oxidase; D020169:Caspases