Cytotoxicity of 1,4-diamino-2-butanone, a putrescine analogue, to RKO cells: mechanism and redox imbalance

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dc.contributor.authorSoares, C. O.
dc.contributor.authorBoiani, M.
dc.contributor.authorMarnett, L. J.
dc.contributor.authorBechara, E. J. H. [UNIFESP]
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionVanderbilt Univ
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T14:34:23Z
dc.date.available2016-01-24T14:34:23Z
dc.date.issued2013-09-01
dc.description.abstractalpha-Aminocarbonyl metabolites (e.g., 5-aminolevulinic acid and aminoacetone) and the wide spectrum microbicide 1,4-diamino-2-butanone (DAB) have been shown to exhibit pro-oxidant properties. in vitro, these compounds undergo phosphate-catalyzed enolization at physiological pH and subsequent superoxide radical-propagated aerobic oxidation, yielding a reactive alpha-oxoaldehyde and H2O2. DAB cytotoxicity to pathogenic microorganisms has been attributed to the inhibition of polyamine biosynthesis. However, the role played in cell death by reactive DAB oxidation products is still poorly understood. This work aims to clarify the mechanism of DAB-promoted pro-oxidant action on mammalian cells. DAB (0.05-10 mM) treatment of RKO cells derived from human colon carcinoma led to a decrease in cell viability (IC50 ca. 0.3 mM DAB, 24 h incubation). Pre-addition of either catalase (5 mu M) or aminoguanidine (20 mM) was observed to partially inhibit the toxic effects of DAB to the cells, while N-acetyl-L-cysteine (NAC, 5 mM) or reduced glutathione (GSH, 5 mM) provided almost complete protection against DAB. Changes in redox balance and stress response pathways were indicated by the increased expression of HO-1, NQO1 and xCT. Moreover, the observation of caspase 3 and PARP cleavage products is consistent with DAB-triggered apoptosis in RKO cells, which was corroborated by the partial protection afforded by the pan-caspase inhibitor z-VAD-FMK. Finally, DAB treatment disrupted the cell cycle in response to increased p53 and activation of ATM. Altogether, these data support the hypothesis that DAB exerts cytotoxicity via a mechanism involving not only polyamine biosynthesis but also by DAB oxidation products.en
dc.description.affiliationUniv São Paulo, Inst Quim, Dept Bioquim, BR-01498 São Paulo, Brazil
dc.description.affiliationVanderbilt Univ, AB Hancock Jr Mem Lab Canc Res, Nashville, TN 37235 USA
dc.description.affiliationUniversidade Federal de São Paulo, Dept Ciencias Exatas & Terra, Inst Ciencias Ambientais Quim & Farmaceut, BR-09972270 Diadema, SP, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Ciencias Exatas & Terra, Inst Ciencias Ambientais Quim & Farmaceut, BR-09972270 Diadema, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipINCT Processos Redox em Biomedicina - Redoxoma
dc.description.sponsorshipNational Institute of Environmental Health Sciences (NIEHS)
dc.description.sponsorshipIDNational Institute of Environmental Health Sciences (NIEHS): 5P01ES013125
dc.format.extent672-682
dc.identifierhttp://dx.doi.org/10.3109/10715762.2013.814126
dc.identifier.citationFree Radical Research. London: Informa Healthcare, v. 47, n. 9, p. 672-682, 2013.
dc.identifier.doi10.3109/10715762.2013.814126
dc.identifier.issn1071-5762
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/36737
dc.identifier.wosWOS:000323107900002
dc.language.isoeng
dc.publisherInforma Healthcare
dc.relation.ispartofFree Radical Research
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://informahealthcare.com/userimages/ContentEditor/1255620309227/Copyright_And_Permissions.pdf
dc.subject1,4-diamino-2-butanoneen
dc.subjectredox imbalanceen
dc.subjectRKO cellsen
dc.subjectapoptosisen
dc.subjecthydrogen peroxideen
dc.subjectalpha-oxoaldehydeen
dc.titleCytotoxicity of 1,4-diamino-2-butanone, a putrescine analogue, to RKO cells: mechanism and redox imbalanceen
dc.typeinfo:eu-repo/semantics/article
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