Non-apoptotic programmed cell death induced by a copper(II) complex in human fibrosarcoma cells

Tardito, Saverio; Bussolati, Ovidio; Gaccioli, Francesca; Gatti, Rita; Guizzardi, Stefano; Uggeri, Jacopo; Marchiò, Luciano; Lanfranchi, Maurizio; Franchi-Gazzola, Renata

doi:10.1007/s00418-006-0183-4

Cited by 47 publications

(55 citation statements)

References 39 publications

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“…To assess the involvement of caspases in the A0-induced cell death, we used specific inhibitors of caspase-3 as well as of other caspases. Consistently with our previous results (18), the cytotoxic effect of A0 was not affected by any of the caspase inhibitors tested (Fig. 1b), whereas the cisplatin-induced decrease of viability was significantly decreased.…”

Section: Differential Sensitivities Of Human Cancer Cells To A0 Andsupporting

confidence: 93%

“…Cisplatin-Previous results from our laboratory have demonstrated that the copper(II) complex A0 causes non-apoptotic death of cancer cells (18). As shown in Fig.…”

Section: Differential Sensitivities Of Human Cancer Cells To A0 Andmentioning

confidence: 94%

“…Cell Viability Assay-Cell viability was assessed with the resazurin assay as previously reported (18). See supplemental methods for the detailed procedure.…”

Section: Methodsmentioning

confidence: 99%

“…Although A0 and cisplatin have comparable potencies in HT1080 human fibrosarcoma cells, the latter induces typical caspase-dependent apoptosis, while A0 inhibits caspase-3 activity and elicits a death process lacking the typical features of apoptosis (18). In contrast, huge vacuoles, derived from the dilatation of the endoplasmic reticulum (ER), 3 are the most evident features of A0-induced cell death, consistently with the induction of a paraptotic process.…”

mentioning

confidence: 99%

“…In contrast, huge vacuoles, derived from the dilatation of the endoplasmic reticulum (ER), 3 are the most evident features of A0-induced cell death, consistently with the induction of a paraptotic process. A possible explanation is that A0, by inhibiting caspase-3 (18), impairs the execution of the apoptotic program, thus addressing the cells to alternative death pathways. Interestingly, recent evidence suggests that paraptosis becomes preponderant when apoptosis executors are somehow inhibited (19).…”

mentioning

confidence: 99%

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The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

123

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The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitinproteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2␣ phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2␣, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2␣ phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2␣ phosphorylation and the UPR.

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Section: Differential Sensitivities Of Human Cancer Cells To A0 Andsupporting

confidence: 93%

“…Cisplatin-Previous results from our laboratory have demonstrated that the copper(II) complex A0 causes non-apoptotic death of cancer cells (18). As shown in Fig.…”

Section: Differential Sensitivities Of Human Cancer Cells To A0 Andmentioning

confidence: 94%

“…Cell Viability Assay-Cell viability was assessed with the resazurin assay as previously reported (18). See supplemental methods for the detailed procedure.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

123

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Synthesis, characterization, DNA binding, apoptosis and molecular docking of three Mn(II), Zn(II) and Cu(II) complexes with terpyridine‐based carboxylic acid

Gao

Feng

et al. 2017

Applied Organom Chemis

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A series of novel cytotoxic compounds, [Mn(cpt)2], [Zn(tpt)(H2O)2]⋅DMA⋅2(H2O) and [Cu(tpt)]⋅DMA (cpt = 4′‐(4‐carboxyphenyl)‐2,2′:6′,2″‐terpyridine, tpt = 4‐(2,4,6‐tricarboxylphenyl)‐2,2′:6′,2″‐terpyridine, DMA = (CH3)2NH), were isolated and characterized. The structures of these complexes were characterized using single‐crystal X‐ray diffraction. The mode and extent of binding between fish sperm DNA and the complexes were investigated using fluorescence spectroscopy and molecular docking. These results indicate the ability of the complexes to bind to DNA with different binding affinities. The binding of the Zn(II) complex with DNA is stronger than that of the corresponding Cu(II) analogue, which is expected due to the z* effect and geometry. The ability of these complexes to cleave pBR322 plasmid DNA was demonstrated using gel electrophoresis assay, showing that the complexes have effective DNA cleavage activity. In addition, the cytotoxic effects of these complexes were examined on HeLa cells (human cervix epithelia carcinoma cells) in vitro. The three complexes exhibit different cytotoxic effects and decent cancer cell inhibitory rate. This means that the structures and type of metal have a great influence on the activity of these novel complexes.

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Tuning biological activity in dinuclear Cu (II) complexes derived from pyrazine ligands: Structure, magnetism, catecholase, antimicrobial, antibiofilm, and antibreast cancer activity

Ahmad

Khalid

Khan

et al. 2021

Applied Organom Chemis

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In a thrust to establish a structure–activity relationship of dinuclear Cu (II) complexes for derived biological activities, two complexes bearing composition [Cu2(pza)2(2‐methoxybenzoate)4] (1) and [Cu2(pza)2(3‐methoxybenzoate)4] (2) are designed. The complexes are characterized thoroughly via single crystal X‐ray diffraction (XRD), spectroscopic, and magnetic analysis. The exact structure of complexes was elucidated as dinuclear bridged by carboxylates with Cu (II) in each complex present in a distorted square‐pyramidal geometry. The ortho and meta substituted benzoates are used in order to investigate its effect on catecholase and other biological activities. The magnetic data on variable temperature dispense the presence of moderate antiferromagnetic interactions in both the complexes with J = −88.7(2) cm−1, R = 2.13 × 10−4 for 1 and J = −86.3(2) cm−1, R = 3.11 × 10−4 for 2 (g = 2.0). As corroborated from UV–visible titrations, cyclic voltammetry (CV), and Electron paramagnetic resonance (EPR) data, the 2 shows enhanced catecholase activity due to higher redox‐active Cu (II) center in 2, which is directly related to the inductive effect of the methoxy substituent. Both the complexes were screened against some bacteria and fungi, and 2 has shown potent activity Escherichia coli. Moreover, the complexes have also shown better antibiofilm properties as compared to their parent salts. The excellent antibreast cancer activity has been observed against MCF‐7 cell line and, 2has greater IC50 (lower activity) than 1. Thus, a structure–activity relationship can further direct us to design other substituted complexes with enhanced biological activity in the future course.

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Non-apoptotic programmed cell death induced by a copper(II) complex in human fibrosarcoma cells

Cited by 47 publications

References 39 publications

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Synthesis, characterization, DNA binding, apoptosis and molecular docking of three Mn(II), Zn(II) and Cu(II) complexes with terpyridine‐based carboxylic acid

Tuning biological activity in dinuclear Cu (II) complexes derived from pyrazine ligands: Structure, magnetism, catecholase, antimicrobial, antibiofilm, and antibreast cancer activity

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