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      An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells

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          Abstract

          Shikonin is a quinone-containing natural product that induces the apoptotic death of some cancer cell lines in culture through increasing intracellular reactive oxygen species (ROS). Quinone-based drugs have shown potential in the clinic, making shikonin an interesting compound to study. Our previous study found that shikonin induces apoptosis in neuroblastoma by induction of ROS, but its mechanism of action and scope of activity are unknown. In this study, we investigated the mode of oxidative stress of shikonin in human glioma cells. ROS induction by shikonin was of mitochondrial origin, as demonstrated by detection of superoxide with MitoSOX Red. Pre-incubation of shikonin with inhibitors of different complexes of the respiratory chain suggested that shikonin-induced ROS production occurred via complex II. In addition, NADPH oxidase and lipooxygenase are two other main ROS-generated sites in shikonin treatment. ROS production by shikonin resulted in the inhibition of nuclear translocation of Nrf2. Stable overexpression of Nrf2 in glioma cells inhibited ROS generation by shikonin. ROS generation from mitochondrial complex II, NADPH oxidase and lipooxygenase is likely the primary mechanism by which shikonin induces apoptosis in glioma cells. These findings also have relevance to the development of certain ROS producers as anti-cancer agents. These, along with shikonin have potential as novel chemotherapeutic agents on human glioma.

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          Reactive oxygen species in cancer cells: live by the sword, die by the sword.

          Reactive oxygen species and tumor biology are intertwined in a complex web, making it difficult to understand which came first, whether oxidants are required for tumor cell growth, and whether oxidant stress can be exploited therapeutically. Evidence suggests that transformed cells use ROS signals to drive proliferation and other events required for tumor progression. This confers a state of increased basal oxidative stress, making them vulnerable to chemotherapeutic agents that further augment ROS generation or that weaken antioxidant defenses of the cell. In this respect, it appears that tumor cells may die by the same systems they require.
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            Reactive oxygen species: role in the development of cancer and various chronic conditions

            Oxygen derived species such as superoxide radical, hydrogen peroxide, singlet oxygen and hydroxyl radical are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. The changes in DNA such as base modification, rearrangement of DNA sequence, miscoding of DNA lesion, gene duplication and the activation of oncogenes may be involved in the initiation of various cancers. Elevated levels of ROS and down regulation of ROS scavengers and antioxidant enzymes are associated with various human diseases including various cancers. ROS are also implicated in diabtes and neurodegenerative diseases. ROS influences central cellular processes such as proliferation a, apoptosis, senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention.
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              Oxidative stress and apoptosis: impact on cancer therapy.

              It is well established that some chemotherapeutic agents and radiation therapy generate reactive oxygen species (ROS) in patients during cancer therapy. Free radicals, particularly ROS have been proposed as common mediators for apoptosis. Recent studies have demonstrated that the mode of cell death depends on the severity of the oxidative damage. This review will address some of the current paradigms of oxidative stress, and antioxidants on apoptosis, and discuss the potential mechanisms by which oxidants can regulate apoptotic pathways. It will also review new developments in eliminating cancer cells by selectively inducing apoptosis. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                8 April 2014
                : 9
                : 4
                : e94180
                Affiliations
                [1 ]Department of Neurosurgery, Chang Gung Memorial Hospital at Chiayi, Chia-Yi 613, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, ROC
                [2 ]Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi City, Taiwan, ROC
                [3 ]Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
                Taipei Medical University, Taiwan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JTY CHC. Performed the experiments: JTY ZLL JYW FJL CHC. Analyzed the data: JTY JYW CHC. Contributed reagents/materials/analysis tools: JTY CHC. Wrote the paper: JTY CHC.

                Article
                PONE-D-13-47665
                10.1371/journal.pone.0094180
                3979747
                24714453
                9af6ece1-1bda-41ca-a899-63c080756bc8
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 November 2013
                : 13 March 2014
                Page count
                Pages: 12
                Funding
                This study was supported by Chang Gung Memorial Hospital, R.O.C. (CMRPG6A0252, J.T.Y.) and in part by National Science Council, Taiwan (NSC 102-2320-B-415-005-MY3; National Science Council's, C.H.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Oxidoreductases
                Plant Biochemistry
                Phytochemicals
                Cell Biology
                Cell Processes
                Cellular Stress Responses
                Molecular Cell Biology
                Medicine and Health Sciences
                Neurology
                Neurological Tumors
                Complementary and Alternative Medicine
                Oncology
                Cancer Prevention
                Cancer Treatment
                Cancers and Neoplasms
                Physical Sciences
                Chemistry
                Phytochemistry
                Phytopharmacology

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                Uncategorized

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