Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis

Sandstrom, Paul; Mannie, Mark D.; Buttke, Thomas M.

doi:10.1002/jlb.55.2.221

Cited by 229 publications

(105 citation statements)

References 42 publications

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“…51 Reduction of ROS by ROS scavenger was able to block apoptosis induced by TNF, anticancer drugs, g-irradiation, and activationinduced cell death in T cells (AICD). 52,53 In this study, we investigated the role of intracellular GSH in determining apoptosis sensitivity and resistance in CD95-resistant cells, in Bcl-x L overexpressing cells, and in hybrids of apoptosis-sensitive and -resistant cells.…”

Section: Introductionmentioning

confidence: 99%

A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells

2004

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In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. Deficiencies in the apoptotic pathways may lead to chemoresistance. Here we report that glutathione (GSH) plays a critical role in activation of apoptosis pathways by CD95 (APO-1/Fas) or anticancer drugs. Upon treatment with anticancer drugs or CD95 triggering, CD95-resistant or Bcl-x L overexpressing CEM cells were deficient in activation of apoptosis pathways. CD95-resistant and Bcl-x L overexpressing CEM cells exhibited higher intracellular GSH levels in comparison to parental cells. Downregulation of GSH by L-buthionine-(S,R)-sulfoxime (BSO), a specific inhibitor of glutathione synthesis, reversed deficiencies in activation of apoptosis pathways by anticancer drugs or CD95. Interestingly, downregulation of GSH by BSO increased CD95 DISC formation in type I cells. In hybrids of CD95-resistant cells with sensitive cells and hybrids of overexpressing Bcl-x L cells with sensitive cells, the phenotype of apoptosis resistance was dominant. Also, in these hybrids, downregulation of GSH reversed CD95-and chemoresistance. We conclude that dominant apoptosis resistance depends, at least in part, on intracellular GSH levels, which may affect apoptosis signaling at different compartments, for example, the death receptor or mitochondria.

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Section: Introductionmentioning

confidence: 99%

A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells

2004

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“…Overexpression of ROS-scavenging enzymes and various antioxidants with ROS-scavenger properties were reported to block apoptosis induced by tumor necrosis factor (TNF), anticancer drugs such as doxorubicin, 39 g-irradiation and activation-induced cell death (AICD). 40 Anti-apoptotic members of the Bcl-2 family have been shown to prevent apoptosis in response to a wide variety of apoptosis stimuli. Overexpression of Bcl-2 or Bcl-X L prevents mitochondrial permeability transition and hyperproduction of ROS by different apoptosis inducing stimuli.…”

Section: Introductionmentioning

confidence: 99%

Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitive- and drug-resistant tumor cells

1999

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Induction of CD95 ligand (CD95-L) may contribute to druginduced apoptosis in chemosensitive leukemias and solid tumors. Here we report that induction of CD95-L and apoptosis by doxorubicin in leukemic and neuroblastoma cells is regulated by the redox state and reactive oxygen species (ROS). Preincubation of chemosensitive cells with antioxidants such as N-acetyl-cysteine (NAC) or glutathione (GSH), significantly reduced doxorubicin-induced apoptosis, hyperexpression of ROS, loss of mitochondrial membrane potential (DC m ) and upregulation of CD95-L expression. Doxorubicinresistant cells exhibited higher levels of GSH in comparison to chemosensitive cells and were deficient in hyperproduction of ROS, loss of DC m and upregulation of CD95-L in response to cytotoxic drugs. Downregulation of intracellular GSH concentrations reversed deficient drug-induced hyperproduction of ROS and CD95-L upregulation. In addition, overexpression of Bcl-X L in CEM cells blocked doxorubicin-triggered ROS and CD95-L expression. These findings suggest that induction of CD95-L by cytotoxic drugs is modulated by the cellular redox state and mitochondria derived ROS.

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“…Indeed, evidence suggests that ROS, which are generated in trace amounts by all aerobic cells, may serve a physiological role in the mediation of cell killing by apoptosis [4][5][6]. Antioxidants, for example, have been reported to block apoptosis [7,8], and the prevention of cell killing by expression of the Bcl-2 proto-oncogene has been attributed to the suppression of cellular ROS [9,10]. The suggested role of ROS in apoptosis, however, and the mechanism by which Bcl-2 is suggested to operate, have been challenged [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Research communication copper-1,10-phenanthroline induces internucleosomal DNA fragmentation in HepG2 cells, resulting from direct oxidation by the hydroxyl radical

Tsang

Tam

Bremner³

et al. 1996

Biochemical Journal

101

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In view of the current speculation regarding the possible role of reactive oxygen species (ROS) in apoptosis, both under physiological conditions and in response to chemicals that promote their intracellular formation, the present investigation was undertaken to examine whether DNA fragmentation during oxidative stress results from endonuclease activity (apoptosis) or from direct attack by ROS. We report that the incubation of HepG2 cells (a human-derived hepatoma cell line) with the copper(II) complex of 1,10-phenanthroline, CuII(OP)2, results in internucleosomal DNA fragmentation, which is widely recognized as being a hallmark of apoptosis. DNA fragmentation did not occur at low temperature, but activity was restored by the addition of ascorbic acid. It is proposed that DNA fragmentation results from the direct attack of hydroxyl radicals upon DNA. Hydroxyl radicals are produced from oxygen by the redox-cycling of CuII(OP)2, which is supported by metabolic processes at normal temperature. At low temperature ascorbic acid provides an artificial cellular reducing environment, thereby restoring hydroxyl radical formation. These findings were confirmed by the detection of internucleosomal DNA fragmentation following the exposure of isolated chromatin to a biomimetic CuII(OP)2 redox-cycling system. We conclude that DNA laddering, the widely employed hallmark of apoptosis, is not unique to endonuclease activity and may also result from direct attack upon DNA by the hydroxyl radical.

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Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis

Cited by 229 publications

References 42 publications

A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells

A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells

Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitive- and drug-resistant tumor cells

Research communication copper-1,10-phenanthroline induces internucleosomal DNA fragmentation in HepG2 cells, resulting from direct oxidation by the hydroxyl radical

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