Diethyldithiocarbamate induces apoptosis in neuroblastoma cells by raising the intracellular copper level, triggering cytochrome c release and caspase activation

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author MATIAS, Andreza C.
MANIERI, Tania M.
CIPRIANO, Samantha S.
CARIONI, Vivian M. O.
NOMURA, Cassiana S.
MACHADO, Camila M. L. FMUSP-HC
CERCHIARO, Giselle
dc.date.issued 2013
dc.identifier.citation TOXICOLOGY IN VITRO, v.27, n.1, p.349-357, 2013
dc.identifier.issn 0887-2333
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/2443
dc.description.abstract Dithiocarbamates are nitrogen- and sulfur-containing compounds commonly used in pharmacology, medicine and agriculture. The molecular effects of dithiocarbamates on neuronal cell systems are not fully understood, especially in terms of their ability to accumulate copper ions inside the cell. In this work, the molecular effects of N,N-diethyldithiocarbamate (DEDTC) were studied in human SH-SY5Y neuroblastoma cells to determine the role of copper in the DEDTC toxicity and the pathway trigged in cell by the complex Cu-DEDTC. From concentration-dependent studies, we found that 5 mu M of this compound induced a drastic decrease in viable cells with a concomitant accumulation in intracellular copper resulted from complexation with DEDTC, measured by atomic absorption spectroscopy. The mechanism of DEDTC-induced apoptosis in neuronal model cells is thought to occur through the death receptor signaling triggered by DEDTC-copper complex in low concentration that is associated with the activation of caspase 8. Our results indicated that the mechanism of cell death involves cytochrome c release forming the apoptosome together with Apaf-1 and caspase 9, converting the caspase 9 into its active form, allowing it to activate caspase 3 as observed by immunofluorescence. This pathway is induced by the cytotoxic effects that occur when DEDTC forms a complex with the copper ions present in the culture medium and transports them into the cell, suggesting that the DEDTC by itself was not able to cause cell death and the major effect is from its copper-complex in neuroblastoma cells. The present study suggests a role for the influence of copper by low concentrations of DEDTC in the extracellular media, the absorption and accumulation of copper in the cell and apoptotic events, induced by the cytotoxic effects that occur when DEDTC forms a complex with the copper ions.
dc.description.sponsorship · Sao Paulo Research Foundation (FAPESP - Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)
· National Council for Scientific and Technological Development (CNPq - Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)
dc.language.iso eng
dc.publisher PERGAMON-ELSEVIER SCIENCE LTD
dc.relation.ispartof Toxicology in Vitro
dc.rights restrictedAccess
dc.subject Diethyldithiocarbamate; Copper uptake; Copper toxicity; Apoptosis; DEDTC; Cytochrome c release; Neuroblastoma; SH-SY5Y
dc.subject.other oxidative stress; pyrrolidine dithiocarbamate; lipid oxidation; myelin injury; n,n-diethyldithiocarbamate; accumulation; involvement; complexes; damage; death
dc.title Diethyldithiocarbamate induces apoptosis in neuroblastoma cells by raising the intracellular copper level, triggering cytochrome c release and caspase activation
dc.type article
dc.rights.holder Copyright PERGAMON-ELSEVIER SCIENCE LTD
dc.description.group LIM/43
dc.identifier.doi 10.1016/j.tiv.2012.08.017
dc.identifier.pmid 22951949
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author MACHADO, Camila M. L.:HC:LIM/43
hcfmusp.author.external · MATIAS, Andreza C.:Fed Univ ABC UFABC, Ctr Nat Sci & Humanities, BR-09210170 Santo Andre, SP, Brazil
· MANIERI, Tania M.:Fed Univ ABC UFABC, Ctr Nat Sci & Humanities, BR-09210170 Santo Andre, SP, Brazil
· CIPRIANO, Samantha S.:Fed Univ ABC UFABC, Ctr Nat Sci & Humanities, BR-09210170 Santo Andre, SP, Brazil
· CARIONI, Vivian M. O.:Fed Univ ABC UFABC, Ctr Nat Sci & Humanities, BR-09210170 Santo Andre, SP, Brazil
· NOMURA, Cassiana S.:Univ Sao Paulo, Inst Chem, BR-05508000 Sao Paulo, Brazil
· CERCHIARO, Giselle:Fed Univ ABC UFABC, Ctr Nat Sci & Humanities, BR-09210170 Santo Andre, SP, Brazil
hcfmusp.origem.id 2-s2.0-84865739076
hcfmusp.origem.id WOS:000314371600041
hcfmusp.publisher.city OXFORD
hcfmusp.publisher.country ENGLAND
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dc.description.index MEDLINE
hcfmusp.citation.wos 20
hcfmusp.affiliation.country Brasil


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