Cytotoxic effects of copper overload on human-derived lung and liver cells in culture

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• 作者：Nathalie Arnal ; Marí ; a J. Tacconi de Alaniz ; Carlos Alberto Marra ; ^{camarra@atlas.med.unlp.edu.ar} ; ^{contactocarlos@hotmail.com}
• 关键词：ATCC ; American Type Culture Collection ; CRP ; ceruloplasmin ; Cu ; copper ; Cu-IUD ; copper-based intrauterine device ; DCF-DA ; dichlorofluerescein-diacetato ; MDA ; malondialdehyde ; MEM ; Eagle's minimum essential medium ; MTT ; 3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-dip
• 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
• 出版年：2012
• 期刊代码：16_03044165
• 类别：bio
• 出版时间：July, 2012
• 卷：1820
• 期：7
• 页码：931-939
• 文件大小：825 K

摘要

Background

Copper (Cu) is an essential trace metal used as a catalytic cofactor for many enzymes. However, it can have nocive effects when it participates in the Fenton reaction, producing reactive oxygen species (ROS). Excess Cu is present in the plasma of patients with diseases in which cell survival is crucial. In order to investigate the effect of Cu overload on the induction of cellular damage we chose two human cell lines derived from liver (HepG2) and lung (A-549) as representative cells exposed to exogenous (polluted air) and/or endogenous (systemic) Cu overload.

Methods

We studied ROS production using thiobarbituric acid reactive substances (TBARS) and fluorimetric measurements with dichlorofluorescein, cell viability by the trypan dye exclusion test, the methyltetrazolium (MTT) and lactate dehydrogenase leakage (LDH) assays, various cytotoxic indexes, and caspasa-3 and calpain-dependent activation as the main signals involved in the apoptosis pathway.

Results

Cu overload induces cell death by a differential activation of calpains (m- and 渭-) and caspase-3, and modifies various proliferative indexes in a cell-type and concentration-dependent manner. The involvement of these two protease systems and the response of the two main Cu homoestatic proteins ceruloplasmin and metallothioneins are specific to each cell type. We demonstrated that Cu can trigger cell death by activation of specific protease systems and modify various proliferative indexes in a cell-type and concentration-dependent manner.

General significance

These findings contribute to understanding the diverse effects of Cu overload on the pathogenesis of human diseases like cancer, cirrhosis and degenerative disorders.