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      Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy

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          Glutathione is the principal intracellular antioxidant buffer against oxidative stress and mainly exists in the forms of reduced glutathione (GSH) and oxidized glutathione (GSSG). The processes of glutathione synthesis, transport, utilization, and metabolism are tightly controlled to maintain intracellular glutathione homeostasis and redox balance. As for cancer cells, they exhibit a greater ROS level than normal cells in order to meet the enhanced metabolism and vicious proliferation; meanwhile, they also have to develop an increased antioxidant defense system to cope with the higher oxidant state. Growing numbers of studies have implicated that altering the glutathione antioxidant system is associated with multiple forms of programmed cell death in cancer cells. In this review, we firstly focus on glutathione homeostasis from the perspectives of glutathione synthesis, distribution, transportation, and metabolism. Then, we discuss the function of glutathione in the antioxidant process. Afterwards, we also summarize the recent advance in the understanding of the mechanism by which glutathione plays a key role in multiple forms of programmed cell death, including apoptosis, necroptosis, ferroptosis, and autophagy. Finally, we highlight the glutathione-targeting therapeutic approaches toward cancers. A comprehensive review on the glutathione homeostasis and the role of glutathione depletion in programmed cell death provide insight into the redox-based research concerning cancer therapeutics.

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          Most cited references 116

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          Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis.

           L Ouyang,  Z. Shi,  S. Zhao (2012)
          Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment. © 2012 Blackwell Publishing Ltd.
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            Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease.

             S Cao,  Randal Kaufman (2014)
            The endoplasmic reticulum (ER) is a specialized organelle for the folding and trafficking of proteins, which is highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Alterations in the protein-folding environment cause accumulation of misfolded proteins in the ER that profoundly affect a variety of cellular signaling processes, including reduction-oxidation (redox) homeostasis, energy production, inflammation, differentiation, and apoptosis. The unfolded protein response (UPR) is a collection of adaptive signaling pathways that evolved to resolve protein misfolding and restore an efficient protein-folding environment. Production of reactive oxygen species (ROS) has been linked to ER stress and the UPR. ROS play a critical role in many cellular processes and can be produced in the cytosol and several organelles, including the ER and mitochondria. Studies suggest that altered redox homeostasis in the ER is sufficient to cause ER stress, which could, in turn, induce the production of ROS in the ER and mitochondria. Although ER stress and oxidative stress coexist in many pathologic states, whether and how these stresses interact is unknown. It is also unclear how changes in the protein-folding environment in the ER cause oxidative stress. In addition, how ROS production and protein misfolding commit the cell to an apoptotic death and contribute to various degenerative diseases is unknown. A greater fundamental understanding of the mechanisms that preserve protein folding homeostasis and redox status will provide new information toward the development of novel therapeutics for many human diseases.
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              Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

              Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

                Author and article information

                Oxid Med Cell Longev
                Oxid Med Cell Longev
                Oxidative Medicine and Cellular Longevity
                10 June 2019
                : 2019
                1School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
                2Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China
                3Zhejiang Heye Health Technology Co. Ltd., Anji, Zhejiang 313300, China
                4Research Centre of Microfluidic Chip for Health Care and Environmental Monitoring, Yangtze River Delta Research Institute of Northwestern Polytechnical University in Taicang, Suzhou, Jiangsu 215400, China
                5Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
                Author notes

                Guest Editor: Kanhaiya Singh

                Copyright © 2019 Huanhuan Lv et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: Northwestern Polytechnical University Foundation for Fundamental Research
                Award ID: 3102018JGC012
                Funded by: Fundamental Research Funds for the Central Universities
                Award ID: 3102017OQD111
                Funded by: National Natural Science Foundation of China
                Award ID: 51777171
                Award ID: 11872316
                Award ID: 81803032
                Review Article

                Molecular medicine


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