Subcellular compartmentalization of glutathione: Correlations with parameters of oxidative stress related to genotoxicity

Green, Richard M.; Graham, Mark; O’Donovan, Michael R.; Chipman, J.K.; Hodges, Nikolas J.

doi:10.1093/mutage/gel043

Cited by 106 publications

(57 citation statements)

References 58 publications

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“…Several analogs with varying degrees of toxicity showed a similar ability to deplete cellular glutathione. As previous reports have established that substantial reductions in glutathione (for example, as induced by the glutathione biosynthesis inhibitor BSO) need not result in cell death, the contribution of glutathione depletion to PL's cellular toxicity remains unclear (20)(21)(22). Additionally, we note that reported estimates of HeLa cell volume (2;600 μm 3 ) (23) and typical concentrations of cellular reduced glutathione (ca.…”

Section: Discussionmentioning

confidence: 86%

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

Adams

Dai

Pellegrino

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

207

221

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Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also contribute to piperlongumine's induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.

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Section: Discussionmentioning

confidence: 86%

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

Adams

Dai

Pellegrino

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

207

221

View full text Add to dashboard Cite

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“…Typically, a small decrease in the transfection activity of pDNA complexes was reported. It is known that BSO inhibits γGCS, which is responsible for the synthesis of the cytosolic GSH pool, leaving the nuclear and mitochondrial pools intact [37]. Since the activity of pDNA complexes might be regulated in part by nuclear GSH, we believe that depleting the total cellular GSH pool with DEM is a better alternative to BSO.…”

Section: Discussionmentioning

confidence: 96%

“…It is also correlated with increased levels of intracellular GSH [28][29][30][31][32][33][34][35]. It has been demonstrated that the increase in GSH levels resulting from overexpression of Bcl-2 is also accompanied by partial redistribution of GSH to the nucleus [36,37]. The increased concentration and changes in subcellular distribution of GSH in cancer cells overexpressing Bcl-2 provide an exciting opportunity for redox-sensitive delivery platforms to selectively enhance the efficiency of cancer gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors

et al. 2008

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Redox-sensitive non-viral delivery systems exploit intracellular reducing environment to improve the efficacy of the delivery of nucleic acids by selectively releasing the cargo in the subcellular space. Bcl-2 overexpression is frequently observed in human cancers and is closely associated with increased resistance to chemotherapy and radiotherapy. One of the biochemical alterations accompanying Bcl-2 overexpression is the increase in cellular glutathione (GSH) levels. In this study, we hypothesize that such increase of GSH concentrations will selectively enhance the transfection activity of redox-sensitive delivery systems in cells overexpressing Bcl-2. Transfection studies were conducted in MCF-7 mammary carcinoma cells and MCF-7 clones overexpressing Bcl-2. It was confirmed that Bcl-2 overexpression resulted in the expected increase in GSH concentrations. Redoxsensitive complexes containing plasmid DNA, mRNA, antisense oligodeoxynucleotides, and siRNA exhibited selectively increased activity in cells overexpressing Bcl-2 compared to non-redox complexes. The effect of Bcl-2 overexpression on the selective enhancement of transfection was highly dependent on the type of the delivered nucleic acid, and was most pronounced for mRNA. This study shows that Bcl-2 overexpression can serve as a proxy redox stimulus to enhance the activity of all major classes of potential nucleic acid therapeutics, when delivered using redoxsensitive vectors.

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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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Subcellular compartmentalization of glutathione: Correlations with parameters of oxidative stress related to genotoxicity

Cited by 106 publications

References 58 publications

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors

Apoptosis and glutathione: beyond an antioxidant

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