Cytotoxic effects of crotamine are mediated through lysosomal membrane permeabilization

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dc.contributor.author Hayashi, Mirian A. F. [UNIFESP]
dc.contributor.author Nascimento, Fabio D. [UNIFESP]
dc.contributor.author Kerkis, Alexandre
dc.contributor.author Oliveira, Vitor [UNIFESP]
dc.contributor.author Oliveira, Eduardo B.
dc.contributor.author Pereira, Alexandre
dc.contributor.author Radis-Baptista, Gandhi
dc.contributor.author Nader, Helena B. [UNIFESP]
dc.contributor.author Yamane, Tetsuo
dc.contributor.author Kerkis, Irina
dc.contributor.author Tersariol, Ivarne L. S. [UNIFESP]
dc.date.accessioned 2016-01-24T13:51:40Z
dc.date.available 2016-01-24T13:51:40Z
dc.date.issued 2008-09-01
dc.identifier http://dx.doi.org/10.1016/j.toxicon.2008.06.029
dc.identifier.citation Toxicon. Oxford: Pergamon-Elsevier B.V., v. 52, n. 3, p. 508-517, 2008.
dc.identifier.issn 0041-0101
dc.identifier.uri http://repositorio.unifesp.br/handle/11600/30888
dc.description.abstract Crotamine, one of the main toxic components of Crotalus durissus terrificus venom, is a small non-enzymatic basic polypeptide, which causes hind limb paralysis and necrosis of muscle cells. it is well-known that several toxins penetrate into the cytosol through endocytosis, although in many cases the mechanism by which this occurs has not been fully investigated. Recently, using low concentrations of crotamine, we demonstrated the uptake of this toxin into actively proliferative cells via endocytosis, an event that ensues crotamine binding to cell membrane heparan sulfate proteoglycans. Thus, crotamine can be regarded as a cell-penetrating peptide that, additionally, has been shown to be able of delivering some biologically active molecules into various cells. Herein, we investigate one of the mechanisms by which crotamine exerts its cytotoxic effects by following its uptake into highly proliferative cells, as CHO-K1 cells. Crotamine accumulation in the acidic endosomal/lysosomal vesicles was observed within 5 min after treatment of these cells with a cytotoxic concentration of this toxin, a value determined here by classical MTT assay. This accumulation caused disruption of lysosomal vesicles accompanied by the leakage of these vesicles contents into the cytosol. This lysosomal lysis also promoted the release of cysteine cathepsin and an increase of caspase activity in the cytoplasm. This chain of events seems to trigger a cell death process. Overall, our data suggest that lysosomes are the primary targets for crotamine cytotoxicity, a proposal corroborated by the correlation between both the kinetics and concentration-dependence of crotamine accumulation in lysosome compartments and the cytotoxic effects of this protein in CHO-K1 cells. Although crotamine is usually regarded as a myotoxin, we observed that intraperitoneal injection of fluorescently labeled crotamine in living mice led to significant and rapid accumulation of this toxin in the cell cytoplasm of several tissues, suggesting that crotamine cytotoxicity might not be restricted to muscle cells. (C) 2008 Elsevier B.V. All rights reserved. en
dc.description.sponsorship Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorship Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.format.extent 508-517
dc.language.iso eng
dc.publisher Elsevier B.V.
dc.relation.ispartof Toxicon
dc.rights Acesso restrito
dc.subject Toxin en
dc.subject Crotamine en
dc.subject Lysosome en
dc.subject Cellular uptake en
dc.subject Cell-penetrating peptides en
dc.subject Highly proliferative cells en
dc.subject Protease en
dc.subject Cytotoxicity en
dc.title Cytotoxic effects of crotamine are mediated through lysosomal membrane permeabilization en
dc.type Artigo
dc.rights.license http://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.contributor.institution Universidade Federal de São Paulo (UNIFESP)
dc.contributor.institution Univ Mogi das Cruzes
dc.contributor.institution Inst Butantan
dc.contributor.institution Clin & Ctr Pesquisa Reprod Humana Roger Abdelmass
dc.contributor.institution Universidade de São Paulo (USP)
dc.contributor.institution Universidade Federal de Pernambuco (UFPE)
dc.description.affiliation Universidade Federal de São Paulo, Dept Farmacol, São Paulo, Brazil
dc.description.affiliation Univ Mogi das Cruzes, Ctr Interdisciplinar Invest Bioquim, BR-08780210 São Paulo, Brazil
dc.description.affiliation Inst Butantan, CAT CEPID, Ctr Toxinol Aplicada, São Paulo, Brazil
dc.description.affiliation Universidade Federal de São Paulo, Dept Bioquim, São Paulo, Brazil
dc.description.affiliation Clin & Ctr Pesquisa Reprod Humana Roger Abdelmass, São Paulo, Brazil
dc.description.affiliation Universidade Federal de São Paulo, Dept Biofis, São Paulo, Brazil
dc.description.affiliation Univ São Paulo, Dept Bioquim & Imunol, BR-14049 Ribeirao Preto, Brazil
dc.description.affiliation Inst Butantan, Genet Lab, São Paulo, Brazil
dc.description.affiliation Univ Fed Pernambuco, Ctr Ciencias Biol, Recife, PE, Brazil
dc.description.affiliation Univ São Paulo, IPEN CNEN SP, BR-09500900 São Paulo, Brazil
dc.description.affiliationUnifesp Universidade Federal de São Paulo, Dept Farmacol, São Paulo, Brazil
dc.description.affiliationUnifesp Universidade Federal de São Paulo, Dept Bioquim, São Paulo, Brazil
dc.description.affiliationUnifesp Universidade Federal de São Paulo, Dept Biofis, São Paulo, Brazil
dc.identifier.doi 10.1016/j.toxicon.2008.06.029
dc.description.source Web of Science
dc.identifier.wos WOS:000260205300012



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