Arsenic trioxide induced indirect and direct inhibition of glutathione reductase leads to apoptosis in rat hepatocytes

Ray, Atish; Chatterjee, Sarmishtha; Mukherjee, Sandip; Bhattacharya, Shelley

doi:10.1007/s10534-014-9722-y

Cited by 13 publications

(11 citation statements)

References 33 publications

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“…DNA damage, PARP cleavage and inhibition of glutathione reductase followed by caspase activation are the marks of cell response to ATO treatment [44]. Our analysis of the DNA damage through evaluation of γ-H2AX histone expression showed that NP realgar and ATO exhibit similar effects preferentially at higher concentration tested.…”

Section: Discussionmentioning

confidence: 70%

“…This myeloid leukemia cell line is often used as a model for terminal hematopoietic differentiation that could be started by realgarinduced increase of intracellular glutathione followed later by the decline to minimum at 6 h. Our study in BOWES and A375 cells revealed the increase of intracellular GSH level at 24 h of the treatment, possibly mediated by the upregulation of NRF2 mRNA as well as its downstream target HO-1, similarly to the reported increase of HO-1, Nrf2, and NFκB in endothelial cells treated by ATO [43]. These results also support the assumption that despite different physical forms of particulate and soluble arsenic, mechanisms of their action are very similar.DNA damage, PARP cleavage and inhibition of glutathione reductase followed by caspase activation are the marks of cell response to ATO treatment [44]. Our analysis of the DNA damage through evaluation of γ-H2AX histone expression showed that NP realgar and ATO exhibit similar effects preferentially at higher concentration tested.…”

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confidence: 70%

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Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Pastorek¹,

Gronesova²,

Cholujová³

et al. 2014

neo

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The aim of the present study was to compare the effect of realgar nanoparticles and arsenic trioxide (ATO) on viability, DNA damage, proliferation, autophagy and apoptosis in the human melanoma cell lines BOWES and A375. The application of various flow cytometric methods for measurements cell viability, DNA cell cycle, mitochondrial potential, lysosomal activity, and intracellular content of glutathione was used. In addition, quantitative PCR, western blotting and multiplex bead array analyses were applied for evaluation of redox stress, autophagic flux, and cell signaling alterations.The results showed that realgar treatment of studied cells caused modulation of cell proliferation, induced a block in G2/M phase of the cell cycle and altered phosphorylation of IκB, Akt, ERK1/2, p38, and JNK kinases, as well as decreased mitochondrial membrane potential. Additionally, it appeared that induction of cell death by both realgar and ATO was dose-dependent, when lower (0.3 µM) dosage increased lysosomal activity and induced autophagy and higher (1.25 µM) concentration resulted in the appearance of apoptosis, while pan-caspase inhibitor attenuated more efficiently realgar-than ATO-induced cell death. Furthermore, low concentrations of ATO and realgar nanoparticles increased the content of intracellular glutathione and elevated γ-H2AX expression confirmed DNA damage preferentially at higher concentrations of both drugs used. Further analysis revealed slight differences in time-dependent phosphorylation pattern due to both realgar and ATO treatments, while significant differences were noticed between cell lines.In conclusion, realgar nanoparticles and ATO treatment induced dose-dependent activation of autophagy and apoptosis in both melanoma cell lines, when autophagy flux was determined at lower drug concentrations and the switch to apoptosis occurred at higher concentrations of both arsenic forms.Key words : realgar, autophagy, cell cycle, DNA damage, Nrf2, chloroquine, glutathione Arsenic has been accepted to be a poison for years and it is generally considered as an extremely effective environmental co-carcinogen for some human malignancies, especially for skin and lung cancer [1]. The toxicity of arsenicals depends on their chemical states, exposure dose, the biological species, age and gender, as well as on individual susceptibilities, genetic and nutritional factors [2]. Largely, to living organisms methylated trivalent arsenicals are more toxic and pentavalent metabolites are less toxic than arsenite (iAs III ) [3,4]. In 2002, a pilot clinical study of pure realgar in treatment of patients with APL was conducted in China, and impressive responses were achieved and reported [5]. Realgar is a mineral composed mainly of tetra-arsenic tetra-sulfide (As 4 S 4 ), which is also called red arsenic due to its a deep red color (Xionghuang in Chinese). Low solubility of arsenic in realgar, using water as a solvent (0.4%), can be increased to approximately 1.5% by leaching in artificial body fluid [6]. Higher proportion of...

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Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 70%

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Pastorek¹,

Gronesova²,

Cholujová³

et al. 2014

neo

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“…Apoptosis is one of the important pathophysiological hallmarks of liver aging and age‐related liver diseases 33,34 . Arsenic‐induced apoptosis has been determined in hepatic tissues and primary hepatocytes 15,16 . However, the potential mechanism of that is still unclear and no effective therapeutic agents have been found.…”

Section: Discussionmentioning

confidence: 99%

“…Epidemiological studies have shown that there is high prevalence of arsenicosis such as skin, 9,10 liver, 11 kidney, 12 lung, 13 and bladder damage 14 . Liver, as one of the important target organs of arsenic toxicity, exhibits an increase of hepatocyte apoptosis in hepatic tissues and primary hepatocytes 15,16 . However, the apoptosis mechanism involved in arsenic poisoning remains unknown.…”

Section: Introductionmentioning

confidence: 99%

ROS‐mediated PERK‐eIF2α‐ATF4 pathway plays an important role in arsenite‐induced L‐02 cells apoptosis via regulating CHOP‐DR5 signaling

Liu

Zhang

2020

Environmental Toxicology

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Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic‐induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated‐ER stress plays an important role in Life‐and‐Death decision of cells. The current study was to investigate whether NaAsO2 utilizes oxidative stress integrated‐ER stress signaling to exert pro‐apoptotic activity in L‐02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO2‐induced apoptosis by enhancing construction of the death‐inducing signaling complex (DISC). NaAsO2‐sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO2 increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R‐like ER kinase (PERK)‐eukaryotic translation initiation 2α (eIF2α)‐activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO2‐induced CHOP and DR5 expressions. In addition, the antioxidant N‐acetyl‐l‐cysteine (NAC) treatment led to amelioration of NaAsO2‐induced production of reactive oxygen species (ROS) and some ER stress‐ and apoptosis‐ related protein levels and cell viability. Taken together, the results indicate that ROS‐mediated PERK‐eIF2α‐ATF4 pathway activated by NaAsO2 is the critical upstream event for subsequent apoptosis induction via regulating CHOP‐DR5 signaling in L‐02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic‐induced hepatotoxicity.

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“…Reagents were added to either the clarified homogenized cell culture containing mAb or to the mAb alone. For enzyme inhibition studies, the concentrations were chosen based on the enzyme's known Ki or IC50 values or according to published references (Grinblat, Sreider, & Stoppani, 1989;Ray, Chatterjee, Mukherjee, & Bhattacharya, 2014;Rigobello et al, 2004;Sadhu, Callegari, Zhao, Guan, & Seefeldt, 2013;Shantz, Talalay, & Gordon, 1989). The TrxR, GR, and Grx inhibitors (ATM, 2-AAPA, nitrofurantoin (NFT), and AsO 2 ) were used at a final concentration of 0.075 mM.…”

Section: Sample Treatment and Purificationmentioning

confidence: 99%

Impact of depth filtration on disulfide bond reduction during downstream processing of monoclonal antibodies from CHO cell cultures

O’Mara

Gao

Kuruganti

et al. 2019

Biotech & Bioengineering

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Monoclonal antibody interchain disulfide bond reduction was observed in a ChineseHamster Ovary manufacturing process that used single-use technologies. A similar reduction has been reported for processes that involved high mechanical shear recovery unit operations, such as continuous flow centrifugation and when the clarified harvest was stored under low dissolved oxygen (DO) conditions (Trexler-Schmidt et al., 2010. Biotechnology and Bioengineering, 106(3), 452-461). The work described here identifies disposable depth filtration used during cell culture harvest operations as a shear-inducing unit operation causing cell lysis. As a result, reduction of antibody interchain disulfide bonds was observed through the same mechanisms described for continuous flow centrifugation. Small-scale depth-filtration models were developed, and the differential pressure (ΔP) of the primary depth filter was identified as the key factor contributing to cell lysis. Strong correlations of ΔP and cell lysis were generated by measuring the levels of lactate dehydrogenase and thiol in the filtered harvest material. A simple risk mitigation strategy was implemented during manufacturing by providing an air overlay to the headspace of a single-use storage bag to maintain sufficient DO in the clarified harvest. In addition, enzymatic characterization studies determined that thioredoxin reductase and glucose-6phosphate dehydrogenase are critical enzymes involved in antibody reduction in a nicotinamide adenine dinucleotide phosphate (NADP + )/NADPH-dependent manner. K E Y W O R D Sair overlay, antibody, cell lysis, depth filtration, differential pressure, dissolved oxygen, disulfide reduction 1 | INTRODUCTION Monoclonal antibodies (mAbs) are commonly manufactured with fed-batch or perfusion mammalian cell culture processes. In such manufacturing processes, the mAb, which is expressed and secreted from the cell, accumulates in the cell culture fluid and is recovered using centrifugation and/or filtration. With the advent of high productivity (>5 g/L) cell culture processes and the availability of improved disposable technologies, the implementation of single-use systems, such as bioreactors, depth filters, columns, membranes, and bioprocess storage bags in the production of biologics has become standard industry practice (Liu, 2005).

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Arsenic trioxide induced indirect and direct inhibition of glutathione reductase leads to apoptosis in rat hepatocytes

Cited by 13 publications

References 33 publications

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

ROS‐mediated PERK‐eIF2α‐ATF4 pathway plays an important role in arsenite‐induced L‐02 cells apoptosis via regulating CHOP‐DR5 signaling

Impact of depth filtration on disulfide bond reduction during downstream processing of monoclonal antibodies from CHO cell cultures

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