The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction

Chen, Q.; Chai, Yoke Chin; Mazumder, Suparna; Jiang, Chenyu; Macklis, Roger M.; Chisolm, Guy M.; Almasan, Alexandru

doi:10.1038/sj.cdd.4401148

Cited by 171 publications

(134 citation statements)

References 46 publications

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“…However, it is possible that CEES initially causes GSH depletion, which may consequently lead to ROS generation. This interpretation is compatible with the caspase activation event that is associated with the increase of ROS production (Chen et al, 2003). Consistent with these observations, GSH-ethyl ester and NAC each inhibited ROS accumulation and the loss of intracellular GSH induced by the SM derivative.…”

Section: Discussionsupporting

confidence: 85%

Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

Han

Espinoza

Liao

et al. 2004

British J Pharmacology

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1 The mechanism of toxicity of sulphur mustard was investigated by examining the biochemical effects of the analog 2-chloroethylethyl sulphide (CEES) in both human Jurkat cells as well as normal human lymphocytes. 2 Exposure of both types of cells to CEES resulted in a marked decrease in the intracellular concentration of the reduced form of glutathione (GSH), and CEES-induced cell death was potentiated by L-buthionine sulphoximine, an inhibitor of GSH synthesis. 3 CEES increased the endogenous production of reactive oxygen species (ROS) in Jurkat cells, and CEES-induced cell death was potentiated by hydrogen peroxide. 4 CEES induced various hallmarks of apoptosis, including collapse of the mitochondrial membrane potential, proteolytic processing and activation of procaspase-3, and cleavage of poly (ADP-ribose) polymerase. 5 The effects of CEES on the accumulation of ROS, the intracellular concentration of GSH, the mitochondrial membrane potential, and caspase-3 activity were all inhibited by pretreatment of cells with the GSH precursor N-acetyl cysteine or with GSH-ethyl ester. Furthermore, CEES-induced cell death was also prevented by these antioxidants. 6 CEES toxicity appears to be mediated, at least in part, by the generation of ROS and consequent depletion of GSH. Given that sulphur mustard is still a potential biohazard, the protective effects of antioxidants against CEES toxicity demonstrated in Jurkat cells and normal human lymphocytes may provide the basis for the development of a therapeutic strategy to counteract exposure to this chemical weapon.

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Section: Discussionsupporting

confidence: 85%

Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

Han

Espinoza

Liao

et al. 2004

British J Pharmacology

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“…This molecule passively diffuses into cells and its chloromethyl group reacts with intra-cellular thiols [22][23][24]. Briefly, cells were treated with either H 2 O 2 (10 μM, 1 h at 37°C as positive control) or PEG-catalase (100 U/ml, 2 h at 37°C), followed by washing and treatment with H 2 O 2 (10 μM, 1 h at 37°C).…”

Section: Reactive Oxygen Species Generationmentioning

confidence: 99%

“…The mitochondrial membrane potential (ΔΨ m ) was measured as described [24]. Briefly, Daudi or Raji cells (5×10 5 per measurement) were stained with DiOC 6 (3) (40 nM in PBS) for 15 min at 37°C and thereafter analyzed for DiOC 6 (3) fluorescence (Ex λ 488±10 nm and Em λ 530±10 nm) by flow cytometry.…”

Section: Mitochondrial Membrane Potentialmentioning

confidence: 99%

Regulation of CD20 expression by radiation-induced changes in intracellular redox status

Gupta

Crosby

Almasan

et al. 2008

Free Radical Biology and Medicine

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Increasing the levels of CD20 expression in cells that harbor low CD20 levels may enhance their responsiveness to CD20-specific antibody therapies. Here, we examined the regulation of CD20 expression after treatment with 0.5-2.0 Gy X-irradiation and hydrogen peroxide (H 2 O 2 ), in the presence or absence of known antioxidants, in the Burkitt lymphoma cell lines Daudi and Raji. Irradiation of cells enhanced cell-surface CD20 expression; the kinetics and extent of this change were cell-type specific and time-dependent. The kinetics of reactive oxygen species generation and changes in mitochondrial membrane potential after irradiation were also correlated with changes in CD20 expression. Raji and Daudi cells treated with H 2 O 2 showed a 2-to 2.5-fold increase in CD20 expression at 12 and 20 h, respectively. Buthionine sulfoximine, which depletes glutathione, also increased surface CD20, whereas antioxidants, such as PEG-catalase, PEG-SOD, vitamin C, and amifostine, decreased CD20 expression induced by radiation or H 2 O 2 . The antioxidant-mediated decrease in CD20 expression induced by radiation or H 2 O 2 suggests a mechanism involving redox regulation. These results demonstrate the critical role of radiationinduced oxidative stress in CD20 expression and may have implications for defining and improving the efficacy of CD20-targeted antibody therapy and radioimmunotherapy. Keywords CD20; Ionizing radiation; Reactive oxygen species; Antioxidants; Mitochondria; Mitochondrial membrane potential; Free radicals The CD20 transmembrane protein is exclusively expressed on B cells. It appears during the pre-B-cell stage, but is absent during the earlier or later stages of B cell differentiation, such as in antibody-secreting plasma cells [1,2]. CD20 has received extensive evaluation as an ideal target for immunotherapy and radioimmunotherapy, in part because of its ubiquitous expression on target cells, stable localization within the cell membrane, and absence from normal stem cells [3]. Rituximab, a chimeric monoclonal anti-CD20 antibody, has been used extensively in the treatment of low-grade B cell lymphomas, such as non-Hodgkin lymphoma (NHL) and other related pathologies. In clinical applications, the efficacy of Rituximab seems to fade after a period of months, leading to Rituximab resistance. The Recent studies have reported that bryostatin-1, interleukin-4, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and interferon-α are all able to induce CD20 surface expression [8][9][10][11][12][13]. However, the mechanisms regulating the expression of CD20 remain poorly understood, even though these cytokines are well known to cause robust intracellular oxidative bursts [14,15]. Recently, it was shown that the bryostatin-1-induced increase of CD20 was regulated at the transcriptional level. The effect of bryostatin-1 on CD20 expression in NHL-derived cells was apparently mediated through the MAPK/ERK signal transduction pathway and involved protein kinase C [13]. Our group has previous...

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“…SDS-PAGE and immunoblotting were performed as described elsewhere [42]. Briefly, the cells or membrane fractions were resuspended in NP-40 containing lysis buffer (10 mM HEPES (pH 7.4), 2 mM EGTA, 0.5% NP-40, 1 mM NaF, 1 mM NaVO 4 , 1 mM phenylmethylsulfonyl fluoride (PMSF), 1 mM DTT, 50 mg/ml trypsin inhibitor, 10 mg/ml aprotinin, and leupeptin) and placed on ice for 30 min.…”

Section: Sds-page and Immunoblottingmentioning

confidence: 99%

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

et al. 2007

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Intracellular redox homeostasis plays a critical role in determining tumor cells' sensitivity to drug-induced apoptosis. Here we investigated the role of thioredoxin-1 (TRX1), a key component of redox regulation, in arsenic trioxide (As 2 O 3 )-induced apoptosis. Over-expression of wild-type TRX1 in HepG 2 cells led to the inhibition of As 2 O 3 -induced cytochrome c (cyto c) release, caspase activation and apoptosis, and down-regulation of TRX1 expression by RNAi sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. Interestingly, mutation of the active site of TRX1 from Cys 32/35 to Ser 32/35 converted this molecule from an apoptotic protector to an apoptotic promoter. In an effort to understand the mechanisms of this conversion, we used isolated mitochondria from mouse liver and found that recombinant wild-type TRX1 could protect mitochondria from the apoptotic changes. In contrast, the mutant form of TRX1 alone elicited mitochondria-related apoptotic changes, including the mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential, and cyto c release from mitochondria. These apoptotic effects were inhibited by cyclosporine A (CsA), indicating that mutant TRX1 targeted to mPTP. Alteration of TRX1 from its reduced form to oxidized form in vivo by 2,4-dinitrochlorobenzene (DNCB), a specific inhibitor of TRX reductase, also sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. These data suggest that TRX1 plays a central role in regulating apoptosis by blocking cyto c release, and inactivation of TRX1 by either mutation or oxidization of the active site cysteines may sensitize tumor cells to As 2 O 3 -induced apoptosis.

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The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction

Cited by 171 publications

References 46 publications

Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

Regulation of CD20 expression by radiation-induced changes in intracellular redox status

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

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