Glutathione depletion‐induced chromosomal DNA fragmentation associated with apoptosis and necrosis

Higuchi, Yoshinori

doi:10.1111/j.1582-4934.2004.tb00470.x

Cited by 182 publications

(116 citation statements)

References 48 publications

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“…Accordingly, our study demonstrates that alantolactone treatment increases the expression of p53 in U87 cells in a time-dependent manner. Other studies have shown that GSH depletion can directly modulate MMP, Bax translocation, and caspases activation, resulting in activation of mitochondrial death cascade (10,29). In this study, alantolactone disrupted MMP and increased the expression of Bax accompanied by a decrease in Bcl-2 expression.…”

Section: Discussionsupporting

confidence: 55%

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

et al. 2012

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Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time‐ and dose‐dependent manner. The alantolactone‐induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl‐2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP‐ribose) polymerase. This alantolactone‐induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N‐acetyl‐L‐cysteine, whereas other antioxidant (polyethylene glycol (PEG)‐catalase and PEG‐superoxide‐dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF‐κB into nucleus; however, NF‐κB inhibitor, SN50 failed to potentiate alantolactone‐induced apoptosis indicating that alantolactone induces NF‐κB‐independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, alantolactone may become a potential lead compound for future development of antiglioma therapy. © © 2012 IUBMB Life, 64(9): 783–794, 2012

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Section: Discussionsupporting

confidence: 55%

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

et al. 2012

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“…This oxidative assault to cells could lead to a decrease in cell proliferation or even leading to cell death via an apoptotic pathway or by necrosis. [13][14][15] To further assess the extent of damage as a result of oxidative assault by SWCNT particles, cell viability was determined after exposing the cells to various concentrations of SWCNT particles. Cytotoxicity was assayed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT, Sigma, St. Louis, MO) dye uptake as described by Manna et al 16 Briefly, HaCaT cells (10 4 cells/well of 96-well plate) were incubated with SWCNT particles in a final volume of 0.1 mL for 72 h at 37 °C.…”

Section: Swcnt Particles Induce Oxidative Stress and Inhibit Cell Promentioning

confidence: 99%

Single-Walled Carbon Nanotube Induces Oxidative Stress and Activates Nuclear Transcription Factor-κB in Human Keratinocytes

et al. 2005

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Carbon nanotubes are now becoming an important material for use in day to day life because of their unique physical properties. The toxicological impact of these materials has not yet been studied in detail, thereby limiting their use. In the present study, the toxicity of single-walled carbon nanotubes (SWCNT) was assessed in human keratinocyte cells. The results show increased oxidative stress and inhibition of cell proliferation in response to treatment of keratinocytes with SWCNT particles. In addition, the signaling mechanism in keratinocytes upon exposure to SWCNT particles was investigated. Results from the study suggest that SWCNT particles activate NF-κB in a dosedependent manner in human keratinocytes. Further, the mechanism of activation of NF-κB was due to the activation of stress-related kinases by SWCNT particles in keratinocytes. In conclusion, these studies show the mechanism of toxicity induced by SWCNT particles.

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“…The nuclear GSH pool is thought to be maintained by the diffusion of GSH into the nucleus across nuclear pores. 66,67 Conjugation of GSH is an essential aspect of xenobiotic and normal physiological metabolism. The glutathione S-transferases (GST) form a class of enzymes with overlapping substrate specificities that generate a large set of thioesthers, called glutathione S-conjugates.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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Glutathione depletion‐induced chromosomal DNA fragmentation associated with apoptosis and necrosis

Cited by 182 publications

References 48 publications

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

Single-Walled Carbon Nanotube Induces Oxidative Stress and Activates Nuclear Transcription Factor-κB in Human Keratinocytes

Apoptosis and glutathione: beyond an antioxidant

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