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      Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications

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          Abstract

          Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H 2O 2) is one of the most studied. Despite the fact that H 2O 2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H 2O 2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H 2O 2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF- α, and NF- κB are also affected by H 2O 2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H 2O 2 may help to decrease the mortality from this malignancy.

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          Most cited references109

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          Free Radicals in Biology and Medicine

          Free Radicals in Biology and Medicine has become a classic text in the field of free radical and antioxidant research. Now in its fifth edition, the book has been comprehensively rewritten and updated whilst maintaining the clarity of its predecessors. Two new chapters discuss 'in vivo' and 'dietary' antioxidants, the first emphasising the role of peroxiredoxins and integrated defence mechanisms which allow useful roles for ROS, and the second containing new information on the role of fruits, vegetables, and vitamins in health and disease. This new edition also contains expanded coverage of the mechanisms of oxidative damage to lipids, DNA, and proteins (and the repair of such damage), and the roles played by reactive species in signal transduction, cell survival, death, human reproduction, defence mechanisms of animals and plants against pathogens, and other important biological events. The methodologies available to measure reactive species and oxidative damage (and their potential pitfalls) have been fully updated, as have the topics of phagocyte ROS production, NADPH oxidase enzymes, and toxicology. There is a detailed and critical evaluation of the role of free radicals and other reactive species in human diseases, especially cancer, cardiovascular, chronic inflammatory and neurodegenerative diseases. New aspects of ageing are discussed in the context of the free radical theory of ageing. This book is recommended as a comprehensive introduction to the field for students, educators, clinicians, and researchers. It will also be an invaluable companion to all those interested in the role of free radicals in the life and biomedical sciences.
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            Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes.

            The metabolism of aerobic organisms continuously produces reactive oxygen species. Although potentially toxic, these compounds also function in signaling. One important feature of signaling compounds is their ability to move between different compartments, e.g. to cross membranes. Here we present evidence that aquaporins can channel hydrogen peroxide (H2O2). Twenty-four aquaporins from plants and mammals were screened in five yeast strains differing in sensitivity toward oxidative stress. Expression of human AQP8 and plant Arabidopsis TIP1;1 and TIP1;2 in yeast decreased growth and survival in the presence of H2O2. Further evidence for aquaporin-mediated H2O2 diffusion was obtained by a fluorescence assay with intact yeast cells using an intracellular reactive oxygen species-sensitive fluorescent dye. Application of silver ions (Ag+), which block aquaporin-mediated water diffusion in a fast kinetics swelling assay, also reversed both the aquaporin-dependent growth repression and the H2O2-induced fluorescence. Our results present the first molecular genetic evidence for the diffusion of H2O2 through specific members of the aquaporin family.
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              Mechanisms of cytochrome c release from mitochondria.

              In healthy cells, cytochrome c (Cyt c) is located in the mitochondrial intermembrane/intercristae spaces, where it functions as an electron shuttle in the respiratory chain and interacts with cardiolipin (CL). Several proapoptotic stimuli induce the permeabilization of the outer membrane, facilitate the communication between intermembrane and intercristae spaces and promote the mobilization of Cyt c from CL, allowing for Cyt c release. In the cytosol, Cyt c mediates the allosteric activation of apoptosis-protease activating factor 1, which is required for the proteolytic maturation of caspase-9 and caspase-3. Activated caspases ultimately lead to apoptotic cell dismantling. Nevertheless, cytosolic Cyt c has been associated also to vital cell functions (i.e. differentiation), suggesting that its release not always occurs in an all-or-nothing fashion and that mitochondrial outer membrane permeabilization may not invariably lead to cell death. This review deals with the events involved in Cyt c release from mitochondria, with special attention to its regulation and final consequences.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi Publishing Corporation
                1942-0900
                1942-0994
                2016
                8 June 2016
                : 2016
                : 1908164
                Affiliations
                1Departamento de Ciencias de la Vida, Universidad de las Fuerzas Armadas (ESPE), Avenida General Rumiñahui, S/N, P.O. Box 171-5-231B, Sangolquí, Ecuador
                2Centro de Nanociencia y Nanotecnología, Universidad de las Fuerzas Armadas (ESPE), Avenida General Rumiñahui, S/N, P.O. Box 171-5-231B, Sangolquí, Ecuador
                3Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK
                4Department of Pharmacology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, 07360 Mexico City, DF, Mexico
                5Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, 07360 Mexico City, DF, Mexico
                Author notes

                Academic Editor: Alexandr V. Bazhin

                Author information
                http://orcid.org/0000-0003-0110-5894
                http://orcid.org/0000-0001-8587-5241
                http://orcid.org/0000-0003-4970-7202
                http://orcid.org/0000-0002-8414-0638
                http://orcid.org/0000-0002-8886-086X
                Article
                10.1155/2016/1908164
                4916325
                27375834
                3a7f4483-e6a9-455b-be44-4902d015d729
                Copyright © 2016 Gabriela Vilema-Enríquez 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.

                History
                : 15 March 2016
                : 10 May 2016
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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