Copper Nanoparticles Induce Oxidative Stress via the Heme Oxygenase 1 Signaling Pathway in vitro Studies

Zou, Li‐Ping; Cheng, Guiping; Xu, Chengcheng; Liu, Heyu; Wang, Yingying; Li, Nianyu; Fan, Xiaoning; Zhu, Changhong; Xia, Wei

doi:10.2147/ijn.s292319

Cited by 30 publications

(15 citation statements)

References 41 publications

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“…Biocompatible agents containing copper in an inorganic form or in the context of metal–organic complexes are widely used in a variety of applications, largely as antibacterial and antifungal drugs, as well as in tumor treatment [ 1 , 2 , 3 , 4 , 5 ]. Copper oxide-based materials varying from sub-10 nm to 40–60 nm (nanoparticles; NPs) and fine (<10 µM) particles have demonstrated cytotoxicity against prokaryotic, yeast, mammalian cell lines and zebrafish embryos [ 6 , 7 , 8 , 9 ]. Coordination of Cu 2+ or Cu 1+ with complex organic scaffolds has yielded a number of perspective multi-targeting chemotypes with differential antitumor properties [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst

Tsymbal

Moiseeva

Agadzhanian

et al. 2021

IJMS

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Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu2+ in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2–3 orders of magnitude determined by IC50 values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1–1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2–6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu–organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu–organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu+1 complexes can generate a superoxide anion in a Fenton-like reaction Cu+1L + O2 → O2−.+ Cu+2L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds.

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Section: Introductionmentioning

confidence: 99%

Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst

Tsymbal

Moiseeva

Agadzhanian

et al. 2021

IJMS

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“…Chakraborty et al demonstrated that CuONPs could stimulate apoptosis in the A-375 cell line (skin cancer cells) via reducing cell membrane rigidity, cleavage of DNA, condensation of chromosomal, arrest of the cell cycle in the G2/M phase, the mitochondrial membrane depolarization, and activation of the caspase-mediated intrinsic pathway. Further investigation revealed that the cancer cell viability and the mitochondrial membrane potential were decreased in the exposure of CuONPs, which resulted in enhancement in the apoptosis rate and induction of oxidative stress 37 , 74 .…”

Section: Resultsmentioning

confidence: 99%

Biogenic copper oxide nanoparticles from Bacillus coagulans induced reactive oxygen species generation and apoptotic and anti-metastatic activities in breast cancer cells

Dolati

Tafvizi

Salehipour

et al. 2023

Sci Rep

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The present study examined the anticancer capabilities of Bacillus coagulans supernatant-produced copper oxide nanoparticles (BC-CuONPs) on MCF-7 and SKBR3 cancer cells. The X-ray diffraction, ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, field-emission scanning electron microscopy, energy-dispersive X-ray, dynamic light scattering, and zeta potential techniques were used to characterize BC-CuONPs. This study also investigated the cellular and molecular processes of NPs’ anti-proliferative and apoptotic properties on human breast cancer cells and compared them to the commercial pharmaceutical tamoxifen. The size of the spherical NP was from 5 to 47 nm with negative zeta potential. The MTT results showed the great cytotoxic effect of BC-CuONPs against breast cancer cells. The BC-CuONPs inhibited the growth of breast cancer cells in a time- and dose-dependent manner. The up-regulation of BCL2-associated X (BAX), cyclin dependent kinase inhibitor 1A (P21), Caspase 3 (CASP3), and Caspase 9 (CASP9), the down-regulation of BCL2 apoptosis regulator (BCL2), Annexin V-FITC/propidium iodide, and reactive oxygen species (ROS) generation results suggested that BC-CuONPs had a significant apoptotic impact when compared to the control. Scratch tests and vascular endothelial growth factor receptor gene (VEGF) down-regulation demonstrated that BC-CuONPs had anti-metastatic activity. The cell cycle analysis and down-regulation of Cyclin D1 (CCND1) and cyclin dependent kinase 4 (CDK4) revealed that cancer cells were arrested in the sub-G1 phase. Finally, the results showed that the secondary metabolites in the supernatant of Bacillus coagulans could form CuONPs, and biogenic BC-CuONPs showed anti-metastasis and anticancer properties on breast cancer cells while having less adverse effects on normal cells. Therefore, the synthesized CuONPs using B. coagulans supernatant can be shown as a potential candidate for a new therapeutic strategy in cancer management.

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“…Oxidative stress is frequently invoked in CuO NP-triggered cell death [ 39 , 40 ] and recent studies have suggested that this effect is mediated by NPs and dissolved ions in tandem [ 41 ]. On the other hand, our previous microarray studies did not provide evidence of significant perturbation of oxidative stress-related pathways following pulmonary exposure to CuO NPs [ 10 , 11 ].…”

Section: Resultsmentioning

confidence: 99%

Copper oxide nanoparticles trigger macrophage cell death with misfolding of Cu/Zn superoxide dismutase 1 (SOD1)

et al. 2022

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Background Copper oxide (CuO) nanoparticles (NPs) are known to trigger cytotoxicity in a variety of cell models, but the mechanism of cell death remains unknown. Here we addressed the mechanism of cytotoxicity in macrophages exposed to CuO NPs versus copper chloride (CuCl2). Methods The mouse macrophage cell line RAW264.7 was used as an in vitro model. Particle uptake and the cellular dose of Cu were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS), respectively. The deposition of Cu in lysosomes isolated from macrophages was also determined by ICP-MS. Cell viability (metabolic activity) was assessed using the Alamar Blue assay, and oxidative stress was monitored by a variety of methods including a luminescence-based assay for cellular glutathione (GSH), and flow cytometry-based detection of mitochondrial superoxide and mitochondrial membrane potential. Protein aggregation was determined by confocal microscopy using an aggresome-specific dye and protein misfolding was determined by circular dichroism (CD) spectroscopy. Lastly, proteasome activity was investigated using a fluorometric assay. Results We observed rapid cellular uptake of CuO NPs in macrophages with deposition in lysosomes. CuO NP-elicited cell death was characterized by mitochondrial swelling with signs of oxidative stress including the production of mitochondrial superoxide and cellular depletion of GSH. We also observed a dose-dependent accumulation of polyubiquitinated proteins and loss of proteasomal function in CuO NP-exposed cells, and we could demonstrate misfolding and mitochondrial translocation of superoxide dismutase 1 (SOD1), a Cu/Zn-dependent enzyme that plays a pivotal role in the defense against oxidative stress. The chelation of copper ions using tetrathiomolybdate (TTM) prevented cell death whereas inhibition of the cellular SOD1 chaperone aggravated toxicity. Moreover, CuO NP-triggered cell death was insensitive to the pan-caspase inhibitor, zVAD-fmk, and to wortmannin, an inhibitor of autophagy, implying that this was a non-apoptotic cell death. ZnO NPs, on the other hand, triggered autophagic cell death. Conclusions CuO NPs undergo dissolution in lysosomes leading to copper-dependent macrophage cell death characterized by protein misfolding and proteasomal insufficiency. Specifically, we present novel evidence for Cu-induced SOD1 misfolding which accords with the pronounced oxidative stress observed in CuO NP-exposed macrophages. These results are relevant for our understanding of the consequences of inadvertent human exposure to CuO NPs.

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Copper Nanoparticles Induce Oxidative Stress via the Heme Oxygenase 1 Signaling Pathway in vitro Studies

Cited by 30 publications

References 41 publications

Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst

Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst

Biogenic copper oxide nanoparticles from Bacillus coagulans induced reactive oxygen species generation and apoptotic and anti-metastatic activities in breast cancer cells

Copper oxide nanoparticles trigger macrophage cell death with misfolding of Cu/Zn superoxide dismutase 1 (SOD1)

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