Glutathione in Cancer Biology and Therapy

Estrela, José M.; Ortega, Ángel; Obrador, Elena

doi:10.1080/10408360500523878

Cited by 895 publications

(513 citation statements)

References 208 publications

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“…35,36 Glutathione is a key regulator of cell death and survival of cancer cells, including leukemia cells. 37,38 PEITC is known to conjugate with GSH, leading to its exportation and depletion of cellular glutathione. This is thought to be a major mechanism of PEITC-induced ROS stress in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Trachootham

Zhang

et al. 2008

Blood

174

173

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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n ‫؍‬ 58) and healthy subjects (n ‫؍‬ 12), we showed that both fludarabineresistant and -sensitive CLL cells were highly sensitive to ␤-phenylethyl isothiocyanate (PEITC) with mean IC 50 values of 5.4 M and 5.1 M, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC 50 ‫؍‬ 27 M, P < .001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

“…38 However, the role of thiol redox status in regulating cell survival remains poorly understood. Under mild oxidative stress, protein glutathionylation was shown to regulate the functions of multiple proteins.…”

Section: Discussionmentioning

confidence: 99%

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Trachootham

Zhang

et al. 2008

Blood

174

173

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“…It is well known that xCT plays a critical role in maintaining intracellular GSH level, whereas GSH is responsible for scavenging harmful intracellular ROS (Estrela et al, 2006). Thus, xCT is essential for maintaining the homeostasis of intracellular ROS.…”

Section: Disruption Of Xct Upregulates Caveolin-1mentioning

confidence: 99%

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

et al. 2008

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xCT, the functional subunit of the cystine/glutamate transporter xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT þ / þ and xCT À/À melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and b-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of b-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

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“…The GSH constitutes the common and main defense system against reactive oxygen species (ROS). This molecule also contributes to detoxification of electrophilic compounds, sequestration of toxic metals and modulation of the cellular redox and thiol-disulfide status of proteins (22).…”

Section: Pro-oxidant Activity In Yeastmentioning

confidence: 99%

Pharmacology and toxicology of diphenyl diselenide in several biological models

Rosa

Roesler

Braga

et al. 2007

Braz J Med Biol Res

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The pharmacology of synthetic organoselenium compounds indicates that they can be used as antioxidants, enzyme inhibitors, neuroprotectors, anti-tumor and anti-infectious agents, and immunomodulators. In this review, we focus on the effects of diphenyl diselenide (DPDS) in various biological model organisms. DPDS possesses antioxidant activity, confirmed in several in vitro and in vivo systems, and thus has a protective effect against hepatic, renal and gastric injuries, in addition to its neuroprotective activity. The activity of the compound on the central nervous system has been studied since DPDS has lipophilic characteristics, increasing adenylyl cyclase activity and inhibiting glutamate and MK-801 binding to rat synaptic membranes. Systemic administration facilitates the formation of long-term object recognition memory in mice and has a protective effect against brain ischemia and on reserpine-induced orofacial dyskinesia in rats. On the other hand, DPDS may be toxic, mainly because of its interaction with thiol groups. In the yeast Saccharomyces cerevisiae, the molecule acts as a pro-oxidant by depleting free glutathione. Administration to mice during cadmium intoxication has the opposite effect, reducing oxidative stress in various tissues. DPDS is a potent inhibitor of δ-aminolevulinate dehydratase and chronic exposure to high doses of this compound has central effects on mouse brain, as well as liver and renal toxicity. Genotoxicity of this compound has been assessed in bacteria, haploid and diploid yeast and in a tumor cell line.

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Glutathione in Cancer Biology and Therapy

Cited by 895 publications

References 208 publications

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

Pharmacology and toxicology of diphenyl diselenide in several biological models

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