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      Bypassing Mechanisms of Mitochondria-Mediated Cancer Stem Cells Resistance to Chemo- and Radiotherapy

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          Abstract

          Cancer stem cells (CSCs) are highly resistant to conventional chemo- and radiotherapeutic regimes. Therefore, the multiple drug resistance (MDR) of cancer is most likely due to the resistance of CSCs. Such resistance can be attributed to some bypassing pathways including detoxification mechanisms of reactive oxygen and nitrogen species (RO/NS) formation or enhanced autophagy. Unlike in normal cells, where RO/NS concentration is maintained at certain threshold required for signal transduction or immune response mechanisms, CSCs may develop alternative pathways to diminish RO/NS levels leading to cancer survival. In this minireview, we will focus on elaborated mechanisms developed by CSCs to attenuate high RO/NS levels. Gaining a better insight into the mechanisms of stem cell resistance to chemo- or radiotherapy may lead to new therapeutic targets thus serving for better anticancer strategies.

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          Identification of selective inhibitors of cancer stem cells by high-throughput screening.

          Piyush B Gupta, Tamer Onder, Guozhi Jiang … (2009)
          Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
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            The thioredoxin antioxidant system.

            Jun Lu, Arne Holmgren (2014)
            The thioredoxin (Trx) system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin, is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance. The Trx system provides the electrons to thiol-dependent peroxidases (peroxiredoxins) to remove reactive oxygen and nitrogen species with a fast reaction rate. Trx antioxidant functions are also shown by involvement in DNA and protein repair by reducing ribonucleotide reductase, methionine sulfoxide reductases, and regulating the activity of many redox-sensitive transcription factors. Moreover, Trx systems play critical roles in the immune response, virus infection, and cell death via interaction with thioredoxin-interacting protein. In mammalian cells, the cytosolic and mitochondrial Trx systems, in which TrxRs are high molecular weight selenoenzymes, together with the glutathione-glutaredoxin (Grx) system (NADPH, glutathione reductase, GSH, and Grx) control the cellular redox environment. Recently mammalian thioredoxin and glutathione systems have been found to be able to provide the electrons crossly and to serve as a backup system for each other. In contrast, bacteria TrxRs are low molecular weight enzymes with a structure and reaction mechanism distinct from mammalian TrxR. Many bacterial species possess specific thiol-dependent antioxidant systems, and the significance of the Trx system in the defense against oxidative stress is different. Particularly, the absence of a GSH-Grx system in some pathogenic bacteria such as Helicobacter pylori, Mycobacterium tuberculosis, and Staphylococcus aureus makes the bacterial Trx system essential for survival under oxidative stress. This provides an opportunity to kill these bacteria by targeting the TrxR-Trx system. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Oxidative stress and cancer: an overview.

              Venus Sosa, Teresa Moliné, Rosa Somoza … (2013)
              Reactive species, which mainly include reactive oxygen species (ROS), are products generated as a consequence of metabolic reactions in the mitochondria of eukaryotic cells. In normal cells, low-level concentrations of these compounds are required for signal transduction before their elimination. However, cancer cells, which exhibit an accelerated metabolism, demand high ROS concentrations to maintain their high proliferation rate. Different ways of developing ROS resistance include the execution of alternative pathways, which can avoid large amounts of ROS accumulation without compromising the energy demand required by cancer cells. Examples of these processes include the guidance of the glycolytic pathway into the pentose phosphate pathway (PPP) and/or the generation of lactate instead of employing aerobic respiration in the mitochondria. Importantly, ROS levels can be used as a thermostat to monitor the damage that cells can bear. The implications for ROS regulation are highly significant for cancer therapy because commonly used radio- and chemotherapeutic drugs influence tumor outcome through ROS modulation. Moreover, the discovery of novel biomarkers that are able to predict the clinical response to pro-oxidant therapies is a crucial challenge to overcome to allow for the personalization of cancer therapies. Copyright © 2012 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oxid Med Cell Longev
                Journal ID (iso-abbrev): Oxid Med Cell Longev
                Journal ID (publisher-id): OMCL
                Title: Oxidative Medicine and Cellular Longevity
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1942-0900
                ISSN (Electronic): 1942-0994
                Publication date (Print): 2016
                Publication date (Electronic): 30 November 2015
                Volume: 2016
                Electronic Location Identifier: 1716341
                Affiliations
                1International Clinical Research Center, St. Anne's University Hospital, Masaryk University, Kamenice 5/A7, 625 00 Brno, Czech Republic
                2Institute of Molecular Biology and Biophysics, Novosibirsk, Russia
                3Oncology and Pathology Group, Institut de Recerca Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
                Author notes
                *Alex Lyakhovich: lyakhovich@ 123456gmail.com and
                *Matilde E. Lleonart: matilde.lleonart@ 123456vhir.org

                Academic Editor: Amit Tyagi

                Article
                DOI: 10.1155/2016/1716341
                PMC ID: 4677234
                PubMed ID: 26697128
                SO-VID: 4e22bec5-08a3-4c0a-a7db-6c144028dc2c
                Copyright © Copyright © 2016 A. Lyakhovich and M. E. Lleonart.
                License:

                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
                Date received : 19 June 2015
                Date revision received : 24 August 2015
                Date accepted : 25 August 2015
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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