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

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

Author Soares, C. O. Google Scholar
Boiani, M. Google Scholar
Marnett, L. J. Google Scholar
Bechara, E. J. H. Autor UNIFESP Google Scholar
Institution Universidade de São Paulo (USP)
Vanderbilt Univ
Universidade Federal de São Paulo (UNIFESP)
Abstract alpha-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.
Keywords 1,4-diamino-2-butanone
redox imbalance
RKO cells
apoptosis
hydrogen peroxide
alpha-oxoaldehyde
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
INCT Processos Redox em Biomedicina - Redoxoma
National Institute of Environmental Health Sciences (NIEHS)
Grant number National Institute of Environmental Health Sciences (NIEHS): 5P01ES013125
Date 2013-09-01
Published in Free Radical Research. London: Informa Healthcare, v. 47, n. 9, p. 672-682, 2013.
ISSN 1071-5762 (Sherpa/Romeo, impact factor)
Publisher Informa Healthcare
Extent 672-682
Origin http://dx.doi.org/10.3109/10715762.2013.814126
Access rights Closed access
Type Article
Web of Science ID WOS:000323107900002
URI http://repositorio.unifesp.br/handle/11600/36737

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