Copper-induced cell death and the protective role of glutathione: the implication of impaired protein folding rather than oxidative stress

Saporito-Magriñá, Christian; Musacco-Sebio, Rosario; Andrieux, Geoffroy; Kook, Lucas; Orrego, Manuel Tomás; Tuttolomondo, María Victoria; Desimone, Martín Federico; Boerries, Melanie; Borner, Christoph; Repetto, Marisa G.

doi:10.1039/c8mt00182k

Cited by 83 publications

(89 citation statements)

References 53 publications

(47 reference statements)

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“…It is known that CuCl 2 salt displays anticancer activity in a range of cancer cells lines, which may be attributed to intracellular Cu overload which leads to ROS production, and altered cancer cell signalling [ 49 , 50 ]. However, despite the disruption of the natural homeostasis of this endogenous metal ion, the cytotoxicity of CuCl 2 is very limited and manifested only at high micromolar concentrations.…”

Section: Investigation Of Mechanism Of Actionmentioning

confidence: 99%

“…While ROS-inducing properties of Cu ions, as well as Cu complexes, have been exhaustively studied, their effects on cancer signalling cascades have been largely overlooked [ 54 ]. Recently, the microarray analysis of Cu-overloaded colon cancer cells revealed the disruption of genes involved in unfolded protein response (UPR), proteasomal degradation and autophagy—the major pro-survival cellular responses [ 49 ]. However, prolonged Cu treatment led to the activation of caspase-dependent and -independent modes of cell death [ 49 ].…”

Section: Investigation Of Mechanism Of Actionmentioning

confidence: 99%

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Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

et al. 2020

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Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL1 and HL2 were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL1 and HL2 with CuCl2·2H2O in 1:1 molar ratio in methanol produced the complexes [CuII(HL1)Cl2]·H2O (1·H2O) and [CuII(HL2)Cl2] (2). The reaction of HL2 with Fe(NO3)3∙9H2O in 2:1 molar ratio in the presence of triethylamine afforded the complex [FeIII(L2)2]NO3∙0.75H2O (3∙0.75H2O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL1, HL2 and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL1 and 1, as well as of HL2 and its complex 2, was monitored as well. Complexes 1−3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL1 and HL2 were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance—leading to the disruption of cancer cell signalling.

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Section: Investigation Of Mechanism Of Actionmentioning

confidence: 99%

Section: Investigation Of Mechanism Of Actionmentioning

confidence: 99%

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

et al. 2020

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“…More likely other adverse processes which have been linked to the cellular presence of CuO-NPs or copper ions liberated from internalized NPs are responsible for the toxicity observed after application of CuO-NPs or CuO-Fe-NPs to C6 cells. Such processes may include the inactivation of cellular enzymes, disturbances of protein folding, protein aggregation, thiol cross-linking as well as impairment of lysosomal functions [68][69][70][71]. The more severe toxicity observed after a treatment of C6 glioma cells with iron-free CuO-NPs compared to CuO-Fe-NPs is likely to be caused by the more rapid release of copper ions from internalized iron-free CuO-NPs, which is associated by a more severe inactivation of crucial cellular processes.…”

Section: Discussionmentioning

confidence: 99%

Iron-Doping of Copper Oxide Nanoparticles Lowers Their Toxic Potential on C6 Glioma Cells

et al. 2020

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Copper oxide nanoparticles (CuO-NPs) are well known for their cytotoxicity which in part has been attributed to the release of copper ions from CuO-NPs. As iron-doping has been reported to reduce the susceptibility of CuO-NPs to dissolution, we have compared pure CuO-NPs and CuO-NPs that had been doped with 10% iron (CuO-Fe-NPs) for copper release and for their toxic potential on C6 glioma cells. Physicochemical characterization revealed that dimercaptosuccinate (DMSA)-coated CuO-NPs and CuO-Fe-NPs did not differ in their size or zeta potential. However, the redox activity and liberation of copper ions from CuO-Fe-NPs was substantially slower compared to that from CuO-NPs, as demonstrated by cyclic voltammetry and by the photometric quantification of the copper ion-bathocuproine complex, respectively. Exposure of C6 cells to these NPs caused an almost identical cellular copper accumulation and each of the two types of NPs induced ROS production and cell toxicity. However, the time-and concentration-dependent loss in cell viability was more severe for cells that had been treated with CuO-NPs compared to cells exposed to CuO-Fe-NPs. Copper accumulation and toxicity after exposure to either CuO-NPs or CuO-Fe-NPs was prevented in the presence of copper chelators, while neutralization of the lysosomal pH by bafilomycin A1 prevented toxicity without affecting cellular copper accumulation or ROS production. These data demonstrate that iron-doping does not affect cellular accumulation of CuO-NPs and suggests that the intracellular liberation of copper ions from CuO-NPs is slowed by the iron doping, which in turn lowers the cell toxic potential of iron-doped CuO-NPs.

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“…The formation of Cu(I)-GSH complex was shown in vitro [ 169 , 207 , 208 ] and one model suggests the formation of a stable (Cu 4 (GSH) 6 ) cluster [ 209 ]. Binding of Cu(I) to GSH is suggested to serve as a protective mechanism in human cell lines [ 210 ]. On the other hand, there is also evidence that Cu(I)–GSH complexes favor the formation of deleterious superoxide in vitro [ 146 ].…”

Section: The Cytosolic Cu Pool: Chaperones Storage Proteins and Cmentioning

confidence: 99%

Cu Homeostasis in Bacteria: The Ins and Outs

et al. 2020

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Copper (Cu) is an essential trace element for all living organisms and used as cofactor in key enzymes of important biological processes, such as aerobic respiration or superoxide dismutation. However, due to its toxicity, cells have developed elaborate mechanisms for Cu homeostasis, which balance Cu supply for cuproprotein biogenesis with the need to remove excess Cu. This review summarizes our current knowledge on bacterial Cu homeostasis with a focus on Gram-negative bacteria and describes the multiple strategies that bacteria use for uptake, storage and export of Cu. We furthermore describe general mechanistic principles that aid the bacterial response to toxic Cu concentrations and illustrate dedicated Cu relay systems that facilitate Cu delivery for cuproenzyme biogenesis. Progress in understanding how bacteria avoid Cu poisoning while maintaining a certain Cu quota for cell proliferation is of particular importance for microbial pathogens because Cu is utilized by the host immune system for attenuating pathogen survival in host cells.

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Copper-induced cell death and the protective role of glutathione: the implication of impaired protein folding rather than oxidative stress

Abstract: Intracellular mechanisms of copper cytotoxicity.

Cited by 83 publications

References 53 publications

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

Iron-Doping of Copper Oxide Nanoparticles Lowers Their Toxic Potential on C6 Glioma Cells

Cu Homeostasis in Bacteria: The Ins and Outs

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