NADPH Oxidase as a Target for Modulation of Radiation Response; Implications to Carcinogenesis and Radiotherapy

Author(s): Keywan Mortezaee, Nasser Hashemi Goradel, Peyman Amini, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Masoud Najafi*, Bagher Farhood*.

Journal Name: Current Molecular Pharmacology

Volume 12 , Issue 1 , 2019

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Graphical Abstract:


Background: Radiotherapy is a treatment modality for cancer. For better therapeutic efficiency, it could be used in combination with surgery, chemotherapy or immunotherapy. In addition to its beneficial therapeutic effects, exposure to radiation leads to several toxic effects on normal tissues. Also, it may induce some changes in genomic expression of tumor cells, thereby increasing the resistance of tumor cells. These changes lead to the appearance of some acute reactions in irradiated organs, increased risk of carcinogenesis, and reduction in the therapeutic effect of radiotherapy.

Discussion: So far, several studies have proposed different targets such as cyclooxygenase-2 (COX-2), some toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) etc., for the amelioration of radiation toxicity and enhancing tumor response. NADPH oxidase includes five NOX and two dual oxidases (DUOX1 and DUOX2) subfamilies that through the production of superoxide and hydrogen peroxide, play key roles in oxidative stress and several signaling pathways involved in early and late effects of ionizing radiation. Chronic ROS production by NOX enzymes can induce genomic instability, thereby increasing the risk of carcinogenesis. Also, these enzymes are able to induce cell death, especially through apoptosis and senescence that may affect tissue function. ROS-derived NADPH oxidase causes apoptosis in some organs such as intestine and tongue, which mediate inflammation. Furthermore, continuous ROS production stimulates fibrosis via stimulation of fibroblast differentiation and collagen deposition. Evidence has shown that in contrast to normal tissues, the NOX system induces tumor resistance to radiotherapy through some mechanisms such as induction of hypoxia, stimulation of proliferation, and activation of macrophages. However, there are some contradictory results. Inhibition of NADPH oxidase in experimental studies has shown promising results for both normal tissue protection and tumor sensitization to ionizing radiation.

Conclusion: In this article, we aimed to review the role of different subfamilies of NADPH oxidase in radiation-induced early and late normal tissue toxicities in different organs.

Keywords: Radiation, radiotherapy, NADPH oxidase, inflammation, genomic instability, fibrosis, tumor resistance, carcinogenesis, ROS, bystander effect.

Goldberg, E.P.; Hadba, A.R.; Almond, B.A.; Marotta, J.S. Intratumoral cancer chemotherapy and immunotherapy: Opportunities for nonsystemic preoperative drug delivery. J. Pharm. Pharmacol., 2002, 54(2), 159-180.
Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, inflammation, and cancer. Cell, 2010, 140(6), 883-899.
Marino, P.; Preatoni, A.; Cantoni, A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta‐analysis. Cancer, 1995, 76(4), 593-601.
Gulley, J.L.; Arlen, P.M.; Bastian, A.; Morin, S.; Marte, J.; Beetham, P.; Tsang, K-Y.; Yokokawa, J.; Hodge, J.W.; Ménard, C. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin. Cancer Res., 2005, 11(9), 3353-3362.
Derer, A.; Frey, B.; Fietkau, R.; Gaipl, U.S. Immune-modulating properties of ionizing radiation: Rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol. Immunother., 2016, 65(7), 779-786.
Golden, E.; Pellicciotta, I.; Demaria, S.; Barcellos-Hoff, M.H.; Formenti, S. The convergence of radiation and immunogenic cell death signaling pathways. Front. Oncology., 2012, 2(88)
Hekim, N.; Cetin, Z.; Nikitaki, Z.; Cort, A.; Saygili, E.I. Radiation triggering immune response and inflammation. Cancer Lett., 2015, 368(2), 156-163.
Formenti, S.C.; Demaria, S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. JNCI., 2013, 105(4), 256-265.
Schaue, D.; Micewicz, E.D.; Ratikan, J.A.; Xie, M.W.; Cheng, G.; McBride, W.H. Radiation & inflammation. Semin. Radiat. Oncol., 2015, 25(1), 4-10.
Yahyapour, R.; Amini, P.; Rezapour, S.; Cheki, M.; Rezaeyan, A.; Farhood, B.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Radiation-induced inflammation and autoimmune diseases. Mil. Med. Res., 2018, 5, 9.
Yahyapour, R.; Shabeeb, D.; Cheki, M.; Musa, A.E.; Farhood, B.; Rezaeyan, A.; Amini, P.; Fallah, H.; Najafi, M. Radiation protection and mitigation by natural antioxidants and flavonoids; Implications to radiotherapy and radiation disasters. Curr. Mol. Pharmacol., 2018, 11(4), 285-304.
Brizel, D.M.; Overgaard, J. Does amifostine have a role in chemoradiation treatment? Lancet Oncol., 2003, 4(6), 378-381.
Rades, D.; Fehlauer, F.; Bajrovic, A.; Mahlmann, B.; Richter, E.; Alberti, W. Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients. Radiother. Oncol., 2004, 70(3), 261-264.
Wasserman, T.H.; Brizel, D.M. The role of amifostine as a radioprotector. Oncology (Williston Park), 2001, 15(10), 1349-1354. discussion 1357-1360.
Amini, P.; Mirtavoos-Mahyari, H.; Motevaseli, E.; Shabeeb, D.; Musa, A.E.; Cheki, M.; Farhood, B.; Yahyapour, R.; Shirazi, A.; Goushbolagh, N.A.; Najafi, M. Mechanisms for radioprotection by melatonin; Can it be used as a radiation countermeasure? Curr. Mol. Pharmacol., 2018.
Davis, T.W.; Hunter, N.; Trifan, O.C.; Milas, L.; Masferrer, J.L. COX-2 inhibitors as radiosensitizing agents for cancer therapy. Am. J. Clin. Oncol., 2003, 26(4), S58-S61.
Alonso-Gonzalez, C.; Gonzalez, A.; Martinez-Campa, C.; Menendez-Menendez, J.; Gomez-Arozamena, J.; Garcia-Vidal, A.; Cos, S. Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis. Cancer Lett., 2016, 370(1), 145-152.
Kolivand, S.; Amini, P.; Saffar, H.; Rezapoor, S.; Motevaseli, E.; Najafi, M.; Nouruzi, F.; Shabeeb, D.; Musa, A.E. Evaluating the radioprotective effect of curcumin on rat’s heart tissues. Curr. Radiopharm., 2018.
Gandhi, S.J.; Minn, A.J.; Vonderheide, R.H.; Wherry, E.J.; Hahn, S.M.; Maity, A. Awakening the immune system with radiation: Optimal dose and fractionation. Cancer Lett., 2015, 368(2), 185-190.
Kaur, P.; Asea, A. Radiation-induced effects and the immune system in cancer. Front. Oncol., 2012, 2, 191.
Shimada, K.; Crother, T.R.; Karlin, J.; Dagvadorj, J.; Chiba, N.; Chen, S.; Ramanujan, V.K.; Wolf, A.J.; Vergnes, L.; Ojcius, D.M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 2012, 36(3), 401-414.
Veiko, N.N. Oxidized extracellular DNA as a stress signal in human cells. Oxid. Med. Cell. Longev., 2013, 2013
Chen, W.; Frank, M.E.; Jin, W.; Wahl, S.M. TGF-β released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity, 2001, 14(6), 715-725.
Li, P-X.; Wong, J.; Ayed, A.; Ngo, D.; Brade, A.M.; Arrowsmith, C.; Austin, R.C.; Klamut, H.J. Placental TGF-β is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J. Biol. Chemist., 2000, 275(26), 20127-20135.
Haberman, Y.; Tickle, T.L.; Dexheimer, P.J.; Kim, M.O.; Tang, D.; Karns, R.; Baldassano, R.N.; Noe, J.D.; Rosh, J.; Markowitz, J.; Heyman, M.B.; Griffiths, A.M.; Crandall, W.V.; Mack, D.R.; Baker, S.S.; Huttenhower, C.; Keljo, D.J.; Hyams, J.S.; Kugathasan, S.; Walters, T.D.; Aronow, B.; Xavier, R.J.; Gevers, D.; Denson, L.A. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest., 2014, 124(8), 3617-3633.
Zhao, W.; Spitz, D.R.; Oberley, L.W.; Robbins, M.E. Redox modulation of the pro-fibrogenic mediator plasminogen activator inhibitor-1 following ionizing radiation. Cancer Res., 2001, 61(14), 5537-5543.
Spitz, D.R.; Azzam, E.I.; Li, J.J.; Gius, D. Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: A unifying concept in stress response biology. Cancer Metastasis Rev., 2004, 23(3-4), 311-322.
Azzam, E.I.; Jay-Gerin, J-P.; Pain, D. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer lett., 2012, 327(1-2), 48-60.
Leach, J.K.; Van Tuyle, G.; Lin, P-S.; Schmidt-Ullrich, R.; Mikkelsen, R.B. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res., 2001, 61(10), 3894-3901.
Robbins, M.; Zhao, W. Chronic oxidative stress and radiation‐induced late normal tissue injury: A review. International journal of radiation biology., 2004, 80(4), 251-259.
Rada, B. Leto, T.L. In: Trends in Innate Immunity; ; Karger Publishers, 2008; 15, pp. 164-187.
Lee, I-T.; Yang, C-M. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem. Pharmacol., 2012, 84(5), 581-590.
Ushio-Fukai, M. Compartmentalization of redox signaling through NADPH oxidase–derived ROS. Antioxid. Redox Signal., 2009, 11(6), 1289-1299.
Archer, S.L.; Reeve, H.L.; Michelakis, E.; Puttagunta, L.; Waite, R.; Nelson, D.P.; Dinauer, M.C.; Weir, E.K. O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. PNAS, 1999, 96(14), 7944-7949.
Chabrashvili, T.; Tojo, A.; Onozato, M.L.; Kitiyakara, C.; Quinn, M.T.; Fujita, T.; Welch, W.J.; Wilcox, C.S. Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension, 2002, 39(2), 269-274.
Dupuy, C.; Ohayon, R.; Valent, A.; Noel-Hudson, M.S.; Deme, D.; Virion, A. Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas. J. Biol. Chem., 1999, 274(52), 37265-37269.
Martyn, K.D.; Frederick, L.M.; von Loehneysen, K.; Dinauer, M.C.; Knaus, U.G. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell. Signal., 2006, 18(1), 69-82.
Ogier-Denis, E.; Mkaddem, S.B.; Vandewalle, A. In. Seminars immunopathol., 2008, 30, 291-300.
Martinez, J.; Malireddi, R.S.; Lu, Q.; Cunha, L.D.; Pelletier, S.; Gingras, S.; Orchard, R.; Guan, J-L.; Tan, H.; Peng, J. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol., 2015, 17(7), 893-906.
Infanger, D.W.; Sharma, R.V.; Davisson, R.L. NADPH oxidases of the brain: Distribution, regulation, and function. Antioxid. Redox Signal., 2006, 8(9-10), 1583-1596.
Bedard, K.; Krause, K-H. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol. Rev., 2007, 87(1), 245-313.
Rokutan, K.; Kawahara, T.; Kuwano, Y.; Tominaga, K.; Nishida, K.; Teshima-Kondo, S. In. Seminars in immunopathology., 2008, 30, 315-327.
Rokutan, K.; Kawahara, T.; Kuwano, Y.; Tominaga, K.; Sekiyama, A.; Teshima-Kondo, S. NADPH oxidases in the gastrointestinal tract: a potential role of Nox1 in innate immune response and carcinogenesis. Antioxid. Redox Signal., 2006, 8(9-10), 1573-1582.
Meitzler, J.L.; Antony, S.; Wu, Y.; Juhasz, A.; Liu, H.; Jiang, G.; Lu, J.; Roy, K.; Doroshow, J.H. NADPH Oxidases: A Perspective on Reactive Oxygen Species Production in Tumor Biology. Antioxid. Redox Signal., 2014, 20(17), 2873-2889.
Krause, K.H. Tissue distribution and putative physiological function of NOX family NADPH oxidases. Japanese . J. Infect. Dis., 2004, 57(5), S28-S29.
Donkó, Á.; Péterfi, Z.; Sum, A.; Leto, T.; Geiszt, M. Dual oxidases. Philosophical Transactions of the Royal Society of London B: Biological Sciences., 2005, 360(1464), 2301-2308.
Trinchieri, G. Cancer and inflammation: An old intuition with rapidly evolving new concepts. Annu. Rev. Immunol., 2012, 30, 677-706.
Shacter, E.; Weitzman, S.A. Chronic inflammation and cancer. Oncology, 2002, 16(2), 217-226. 229; discussion 230-212.
Thun, M.J.; Henley, S.J.; Gansler, T. Inflammation and cancer: An epidemiological perspective. Novartis Found. Symp., 2004, 256, 6-21.
Shivappa, N.; Hebert, J.R.; Rosato, V.; Garavello, W.; Serraino, D.; La Vecchia, C. Inflammatory potential of diet and risk of oral and pharyngeal cancer in a large case-control study from Italy. Int. J. Cancer, 2017, 141(3), 471-479.
Yahyapour, R.; Motevaseli, E.; Rezaeyan, A.; Abdollahi, H.; Farhood, B.; Cheki, M.; Najafi, M.; Villa, V. Mechanisms of radiation bystander and non-targeted effects: Implications to radiation carcinogenesis and radiotherapy. Curr. Radiopharm., 2018, 11(1), 34-45.
Rhee, S.G.; Chang, T-S.; Bae, Y.S.; Lee, S-R.; Kang, S.W. Cellular regulation by hydrogen peroxide. Journal of the American Society of Nephrology., 2003, 14(Suppl. 3), S211-S215.
Fan, C.Y.; Katsuyama, M.; Yabe-Nishimura, C. PKCδ mediates up-regulation of NOX1, a catalytic subunit of NADPH oxidase, via transactivation of the EGF receptor: Possible involvement of PKCδ in vascular hypertrophy. Biochem. J., 2005, 390(3), 761-767.
Fan, C.; Katsuyama, M.; Nishinaka, T.; Yabe-Nishimura, C. Transactivation of the EGF receptor and a PI3 kinase–ATF‐1 pathway is involved in the upregulation of NOX1, a catalytic subunit of NADPH oxidase. FEBS letters., 2005, 579(5), 1301-1305.
Bae, Y.S.; Kang, S.W.; Seo, M.S.; Baines, I.C.; Tekle, E.; Chock, P.B.; Rhee, S.G. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide Role in EGF receptor-mediated tyrosine phosphorylation. J. Biol. Chem., 1997, 272(1), 217-221.
Colotta, F.; Allavena, P.; Sica, A.; Garlanda, C.; Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis, 2009, 30(7), 1073-1081.
Martinez-Outschoorn, U.E.; Balliet, R.M.; Rivadeneira, D.; Chiavarina, B.; Pavlides, S.; Wang, C.; Whitaker-Menezes, D.; Daumer, K.; Lin, Z.; Witkiewicz, A. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle, 2010, 9(16), 3276-3296.
Chiera, F.; Meccia, E.; Degan, P.; Aquilina, G.; Pietraforte, D.; Minetti, M.; Lambeth, D.; Bignami, M. Overexpression of human NOX1 complex induces genome instability in mammalian cells. Free Radic. Biol. Med., 2008, 44(3), 332-342.
Puca, R.; Nardinocchi, L.; Starace, G.; Rechavi, G.; Sacchi, A.; Givol, D.; D’Orazi, G. Nox1 is involved in p53 deacetylation and suppression of its transcriptional activity and apoptosis. Free Radic. Biol. Med., 2010, 48(10), 1338-1346.
MacFie, T.S.; Poulsom, R.; Parker, A.; Warnes, G.; Boitsova, T.; Nijhuis, A.; Suraweera, N.; Poehlmann, A.; Szary, J.; Feakins, R.; Jeffery, R.; Harper, R.W.; Jubb, A.M.; Lindsay, J.O.; Silver, A. DUOX2 and DUOXA2 form the predominant enzyme system capable of producing the reactive oxygen species H2O2 in active ulcerative colitis and are modulated by 5-aminosalicylic acid. Inflamm. Bowel Dis., 2014, 20(3), 514-524.
Davies, G.R.; Simmonds, N.J.; Stevens, T.R.; Grandison, A.; Blake, D.R.; Rampton, D.S. Mucosal reactive oxygen metabolite production in duodenal ulcer disease. Gut, 1992, 33(11), 1467-1472.
Roy, K.; Wu, Y.; Meitzler, J.L.; Juhasz, A.; Liu, H.; Jiang, G.; Lu, J.; Antony, S.; Doroshow, J.H. NADPH oxidases and cancer. Clin. Sci. (Lond.), 2015, 128(12), 863-875.
Han, M.; Zhang, T.; Yang, L.; Wang, Z.; Ruan, J.; Chang, X. Association between NADPH oxidase (NOX) and lung cancer: A systematic review and meta-analysis. J. Thorac. Dis., 2016, 8(7), 1704-1711.
Suh, Y.A.; Arnold, R.S.; Lassegue, B.; Shi, J.; Xu, X.; Sorescu, D.; Chung, A.B.; Griendling, K.K.; Lambeth, J.D. Cell transformation by the superoxide-generating oxidase Mox1. Nature, 1999, 401(6748), 79-82.
Naughton, R.; Quiney, C.; Turner, S.D.; Cotter, T.G. Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway. Leukemia, 2009, 23(8), 1432-1440.
Graham, K.A.; Kulawiec, M.; Owens, K.M.; Li, X.; Desouki, M.M.; Chandra, D.; Singh, K.K. NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol. Ther., 2010, 10(3), 223-231.
Yahyapour, R.; Motevaseli, E.; Rezaeyan, A.; Abdollahi, H.; Farhood, B.; Cheki, M.; Rezapoor, S.; Shabeeb, D.; Musa, A.E.; Najafi, M.; Villa, V. Reduction-oxidation (redox) system in radiation-induced normal tissue injury: Molecular mechanisms and implications in radiation therapeutics. Clin. Transl. Oncol., 2018, 20(8), 975-988.
Najafi, M.; Motevaseli, E.; Shirazi, A.; Geraily, G.; Rezaeyan, A.; Norouzi, F.; Rezapoor, S.; Abdollahi, H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: Clinical implications. Int. J. Radiat. Biol., 2018, 94(4), 335-356.
Farhood, B.; Goradel, N.H.; Mortezaee, K.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Intercellular communications-redox interactions in radiation toxicity; Potential targets for radiation mitigation. J. Cell Commun. Signal., 2018.
Dikalov, S. Cross talk between mitochondria and NADPH oxidases. Free Radic. Biol. Med., 2011, 51(7), 1289-1301.
Daiber, A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim. Biophys. Acta, 2010, 1797(6-7), 897-906.
Daiber, A.; Di Lisa, F.; Oelze, M.; Kroller-Schon, S.; Steven, S.; Schulz, E.; Munzel, T. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. Br. J. Pharmacol., 2017, 174(12), 1670-1689.
Weyemi, U.; Redon, C.E.; Aziz, T.; Choudhuri, R.; Maeda, D.; Parekh, P.R.; Bonner, M.Y.; Arbiser, J.L.; Bonner, W.M. Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage. Radiat. Res., 2015, 183(3), 262-270.
Wang, Y.; Liu, L.; Pazhanisamy, S.K.; Li, H.; Meng, A.; Zhou, D. Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic. Biol. Med., 2010, 48(2), 348-356.
Pazhanisamy, S.K.; Li, H.; Wang, Y.; Batinic-Haberle, I.; Zhou, D. NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability. Mutagenesis, 2011, 26(3), 431-435.
Chang, J.; Feng, W.; Wang, Y.; Luo, Y.; Allen, A.R.; Koturbash, I.; Turner, J.; Stewart, B.; Raber, J.; Hauer-Jensen, M.; Zhou, D.; Shao, L. Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice. Radiat. Res., 2015, 183(2), 240-248.
Choi, K.M.; Kang, C.M.; Cho, E.S.; Kang, S.M.; Lee, S.B.; Um, H.D. Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK. Oncol. Rep., 2007, 17(5), 1183-1188.
Zhang, H.; Wang, Y-a.; Meng, A.; Yan, H.; Wang, X.; Niu, J.; Li, J.; Wang, H. Inhibiting TGFβ1 has a protective effect on mouse bone marrow suppression following ionizing radiation exposure in vitro. J. Radiat. Res., 2013, 54(4), 630-636.
Li, D.; Tian, Z.; Tang, W.; Zhang, J.; Lu, L.; Sun, Z.; Zhou, Z.; Fan, F. The Protective effects of 5-methoxytryptamine-α-lipoic acid on ionizing radiation-induced hematopoietic injury. Int. J. Mol. Sci., 2016, 17(6), 935.
Long, W.; Zhang, G.; Dong, Y.; Li, D. Dark tea extract mitigates hematopoietic radiation injury with antioxidative activity. J. Radiat. Res., 2018, 59(4), 387-394.
Zhang, H.; Zhai, Z.; Wang, Y.; Zhang, J.; Wu, H.; Wang, Y.; Li, C.; Li, D.; Lu, L.; Wang, X.; Chang, J.; Hou, Q.; Ju, Z.; Zhou, D.; Meng, A. Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic. Biol. Med., 2013, 54, 40-50.
Xu, G.; Wu, H.; Zhang, J.; Li, D.; Wang, Y.; Wang, Y.; Zhang, H.; Lu, L.; Li, C.; Huang, S.; Xing, Y.; Zhou, D.; Meng, A. Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic. Biol. Med., 2015, 87, 15-25.
Ameziane-El-Hassani, R.; Talbot, M.; de Souza Dos Santos, M.C.; Al Ghuzlan, A.; Hartl, D.; Bidart, J-M.; De Deken, X.; Miot, F.; Diallo, I.; de Vathaire, F.; Schlumberger, M.; Dupuy, C. NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. PNAS, 2015, 112(16), 5051-5056.
Tateishi, Y.; Sasabe, E.; Ueta, E.; Yamamoto, T. Ionizing irradiation induces apoptotic damage of salivary gland acinar cells via NADPH oxidase 1-dependent superoxide generation. Biochem. Biophys. Res. Commun., 2008, 366(2), 301-307.
Wang, Y.; Liu, Q.; Zhao, W.; Zhou, X.; Miao, G.; Sun, C.; Zhang, H. NADPH Oxidase Activation Contributes to Heavy Ion Irradiation-Induced Cell Death. Dose Res., 2017, 15(1), 1559325817699697.
Sun, C.; Wang, Z.; Liu, Y.; Liu, Y.; Li, H.; Di, C.; Wu, Z.; Gan, L.; Zhang, H. Carbon ion beams induce hepatoma cell death by NADPH oxidase-mediated mitochondrial damage. J. Cell. Physiol., 2014, 229(1), 100-107.
Yamaguchi, M.; Kashiwakura, I. Role of Reactive Oxygen Species in the Radiation Response of Human Hematopoietic Stem/Progenitor Cells. Plos One, 2013, 8(7), e70503.
Cali, B.; Ceolin, S.; Ceriani, F.; Bortolozzi, M.; Agnellini, A.H.; Zorzi, V.; Predonzani, A.; Bronte, V.; Molon, B.; Mammano, F. Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury. Oncotarget, 2015, 6(12), 10161-10174.
Chai, Y.; Calaf, G.M.; Zhou, H.; Ghandhi, S.A.; Elliston, C.D.; Wen, G.; Nohmi, T.; Amundson, S.A.; Hei, T.K. Radiation induced COX-2 expression and mutagenesis at non-targeted lung tissues of gpt delta transgenic mice. Br. J. Cancer, 2013, 108(1), 91-98.
Little, J.; Azzam, E.; De Toledo, S.; Nagasawa, H. Bystander effects: Intercellular transmission of radiation damage signals. Radiat.Protect Dos., 2002, 99(1-4), 159-162.
Liu, S.; Jin, S.; Liu, X-D. Radiation-induced bystander effect in immune response. Biomed. Environ. Sci., 2004, 17(1), 40-46.
Narayanan, P.K.; Goodwin, E.H.; Lehnert, B.E. Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. Cancer Res., 1997, 57(18), 3963-3971.
Azzam, E.I.; De Toledo, S.M.; Spitz, D.R.; Little, J.B. Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res., 2002, 62(19), 5436-5442.
Sergeeva, V.A.; Ershova, E.S.; Veiko, N.N.; Malinovskaya, E.M.; Kalyanov, A.A.; Kameneva, L.V.; Stukalov, S.V.; Dolgikh, O.A.; Konkova, M.S.; Ermakov, A.V.; Veiko, V.P.; Izhevskaya, V.L.; Kutsev, S.I.; Kostyuk, S.V. Low-dose ionizing radiation affects mesenchymal stem cells via extracellular oxidized cell-free DNA: A possible mediator of bystander Effect and adaptive response. Oxid. Med. Cell. Longev., 2017, 2017, 9515809.
Temme, J.; Bauer, G. Low-dose gamma irradiation enhances superoxide anion production by nonirradiated cells through TGF-beta1-dependent bystander signaling. Radiat. Res., 2013, 179(4), 422-432.
Morgan, W.F.; Sowa, M.B. Non-targeted bystander effects induced by ionizing radiation. Mutat. Res., 2007, 616(1-2), 159-164.
Cheki, M.; Yahyapour, R.; Farhood, B.; Rezaeyan, A.; Shabeeb, D.; Amini, P.; Rezapoor, S.; Najafi, M. COX-2 in Radiotherapy: A Potential Target for Radioprotection and Radiosensitization. Curr. Mol. Pharmacol., 2018, 11(3), 173-183.
Yahyapour, R.; Salajegheh, A.; Safari, A.; Amini, P.; Rezaeyan, A.; Amraee, A.; Najafi, M. Radiation-induced non-targeted effect and carcinogenesis; implications in clinical radiotherapy. J. Biomed. Phys. Eng., 8(4)2018, , 435-446.
Hamada, N.; Maeda, M.; Otsuka, K.; Tomita, M. Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects. Curr. Mol. Pharmacol., 2011, 4(2), 79-95.
Jiang, Y.; Chen, X.; Tian, W.; Yin, X.; Wang, J.; Yang, H. The role of TGF-β1–miR-21–ROS pathway in bystander responses induced by irradiated non-small-cell lung cancer cells. Br. J. Cancer, 2014, 111(4), 772-780.
Szatmári, T.; Kis, D.; Bogdándi, E.N.; Benedek, A.; Bright, S.; Bowler, D.; Persa, E.; Kis, E.; Balogh, A.; Naszályi, L.N.; Kadhim, M.; Sáfrány, G.; Lumniczky, K. Extracellular vesicles mediate radiation-induced systemic bystander signals in the bone marrow and spleen. Front. Immunol., 2017, 8(347)
Cagin, Y.F.; Parlakpinar, H.; Polat, A.; Vardi, N.; Atayan, Y.; Erdogan, M.A.; Ekici, K.; Yildiz, A.; Sarihan, M.E.; Aladag, H. The protective effects of apocynin on ionizing radiation-induced intestinal damage in rats. Drug Dev. Ind. Pharm., 2016, 42(2), 317-324.
Su, L.; Wang, Z.; Huang, F.; Lan, R.; Chen, X.; Han, D.; Zhang, L.; Zhang, W.; Hong, J. 18β-Glycyrrhetinic acid mitigates radiation-induced skin damage via NADPH oxidase/ROS/p38MAPK and NF-κB pathways. Environ. Toxicol. Pharmacol., 2018, 60, 82-90.
Sakai, Y.; Yamamori, T.; Yoshikawa, Y.; Bo, T.; Suzuki, M.; Yamamoto, K.; Ago, T.; Inanami, O. NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells. Free Radic. Res., 2018, 52(1), 92-102.
Cho, H.J.; Lee, W.H.; Hwang, O.M.H.; Sonntag, W.E.; Lee, Y.W. Role of NADPH oxidase in radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain. Int. J. Radiat. Biol., 2017, 93(11), 1257-1266.
Collins-Underwood, J.R.; Zhao, W.; Sharpe, J.G.; Robbins, M.E. NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells. Free Radic. Biol. Med., 2008, 45(6), 929-938.
Chatterjee, A.; Kosmacek, E.A.; Oberley-Deegan, R.E. MnTE-2-PyP treatment, or NOX4 inhibition, protects against radiation-induced damage in mouse primary prostate fibroblasts by inhibiting the tgf-beta 1 signaling pathway. Radiat. Res., 2017, 187(3), 367-381.
Park, S.; Ahn, J-Y.; Lim, M-J.; Kim, M-H.; Yun, Y-S.; Jeong, G.; Song, J-Y. Sustained expression of NADPH oxidase 4 by p38 MAPK-Akt signaling potentiates radiation-induced differentiation of lung fibroblasts. J. Mol. Med. (Berl.), 2010, 88(8), 807-816.
Hong, E.H.; Lee, S.J.; Kim, J.S.; Lee, K.H.; Um, H.D.; Kim, J.H.; Kim, S.J.; Kim, J.I.; Hwang, S.G. Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase. J. Biol. Chem., 2010, 285(2), 1283-1295.
Choi, S.H.; Kim, M.; Lee, H.J.; Kim, E.H.; Kim, C.H.; Lee, Y.J. Effects of NOX1 on fibroblastic changes of endothelial cells in radiationinduced pulmonary fibrosis. Mol. Med. Rep., 2016, 13(5), 4135-4142.
Citrin, D.E.; Shankavaram, U.; Horton, J.A.; Shield, W.; Zhao, S.; Asano, H.; White, A.; Sowers, A.; Thetford, A.; Chung, E.J. Role of Type II Pneumocyte Senescence in Radiation-Induced Lung Fibrosis. JNCI., 2013, 105(19), 1474-1484.
Chen, C.; Yang, S.; Zhang, M.; Zhang, Z.; Hong, J.; Han, D.; Ma, J.; Zhang, S.B.; Okunieff, P.; Zhang, L. Triptolide mitigates radiation-induced pulmonary fibrosis via inhibition of axis of alveolar macrophages-NOXes-ROS-myofibroblasts. Cancer Biol. Ther., 2016, 17(4), 381-389.
Marengo, B.; Nitti, M.; Furfaro, A.L.; Colla, R.; Ciucis, C.D.; Marinari, U.M.; Pronzato, M.A.; Traverso, N.; Domenicotti, C. redox homeostasis and cellular antioxidant systems: Crucial players in cancer growth and therapy. Oxid. Med. Cell Longev., 2016, 2016
Zhang, L.; Li, J.; Zong, L.; Chen, X.; Chen, K.; Jiang, Z.; Nan, L.; Li, X.; Li, W.; Shan, T.; Ma, Q.; Ma, Z. Reactive Oxygen Species and Targeted Therapy for Pancreatic Cancer. Oxid. Med. Cell. Longev., 2016, 2016, 1-9.
Liou, G-Y.; Storz, P. Reactive oxygen species in cancer. Free radical research., 2010, 44(5)
Kumari, S.; Badana, A.K. G, M.M.; G, S.; Malla, R. Reactive oxygen species: A key constituent in cancer survival. Biomarker . Insights, 2018, 13, 1177271918755391.
Umansky, V.; Schirrmacher, V. Nitric oxide-induced apoptosis in tumor cells. Adv. Cancer Res., 2001, 82, 107-131.
delaTorre, A.; Schroeder, R.A.; Bartlett, S.T.; Kuo, P.C. Differential effects of nitric oxide-mediated S-nitrosylation on p50 and c-jun DNA binding. Surgery, 1998, 124(2), 137-141.
Yamamoto, Y.; Gaynor, R.B. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J. Clin. Invest., 2001, 107(2), 135-142.
Bonavida, B. In: Nitric Oxide (Donor/Induced) in Chemosensitizing; Bonavida, B., Ed.; Academic Press, 2017; pp. 15-34.
Wolff, S. The adaptive response in radiobiology: Evolving insights and implications. Environ. Health Perspect., 1998, 106(Suppl. 1), 277-283.
Zhao, X.; Cui, J.W.; Hu, J.H.; Gao, S.J.; Liu, X.L. Effects of low-dose radiation on adaptive response in colon cancer stem cells. Clin. Transl. Oncol., 2017, 19(7), 907-914.
Semenza, G.L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene, 2010, 29(5), 625-634.
Eales, K.L.; Hollinshead, K.E.R.; Tennant, D.A. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis, 2016, 5, e190.
Zhang, C.; Lan, T.; Hou, J.; Li, J.; Fang, R.; Yang, Z.; Zhang, M.; Liu, J.; Liu, B. NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling. Oncotarget, 2014, 5(12), 4392-4405.
You, X.; Ma, M.; Hou, G.; Hu, Y.; Shi, X. Gene expression and prognosis of NOX family members in gastric cancer. OncoTargets Ther., 2018, 11, 3065-3074.
Lu, J.P.; Monardo, L.; Bryskin, I.; Hou, Z.F.; Trachtenberg, J.; Wilson, B.C.; Pinthus, J.H. Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase. Prostate Cancer Prostatic Dis., 2010, 13(1), 39-46.
Hsieh, C.H.; Wu, C.P.; Lee, H.T.; Liang, J.A.; Yu, C.Y.; Lin, Y.J. NADPH oxidase subunit 4 mediates cycling hypoxia-promoted radiation resistance in glioblastoma multiforme. Free Radic. Biol. Med., 2012, 53(4), 649-658.
Hsieh, C.H.; Lee, C.H.; Liang, J.A.; Yu, C.Y.; Shyu, W.C. Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity. Oncol. Rep., 2010, 24(6), 1629-1636.
Pei, H.; Zhang, J.; Nie, J.; Ding, N.; Hu, W.; Hua, J.; Hirayama, R.; Furusawa, Y.; Liu, C.; Li, B.; Hei, T.K.; Zhou, G. RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation. Cell Cycle, 2017, 16(1), 113-122.
Ludwig, K.; Belle, J.L.; Sperry, J.; Vlashi, E.; Pajonk, F.; Kornblum, H. RBIO-06. NADPH oxidase (NOX) promotes radiation resistance through oxidation of pten in glioblastoma. Neuro. Oncol., 2017, 19((suppl_6)), vi218.
Wu, Q.; Allouch, A.; Paoletti, A.; Leteur, C.; Mirjolet, C.; Martins, I.; Voisin, L.; Law, F.; Dakhli, H.; Mintet, E.; Thoreau, M.; Muradova, Z.; Gauthier, M.; Caron, O.; Milliat, F.; Ojcius, D.M.; Rosselli, F.; Solary, E.; Modjtahedi, N.; Deutsch, E.; Perfettini, J.L. NOX2-dependent ATM kinase activation dictates pro-inflammatory macrophage phenotype and improves effectiveness to radiation therapy. Cell Death Differ., 2017, 24(9), 1632-1644.
Nguyen, D.M.; Parekh, P.R.; Chang, E.T.; Sharma, N.K.; Carrier, F. Contribution of Dual Oxidase 2 (DUOX2) to Hyper-Radiosensitivity in Human Gastric Cancer Cells. Radiat. Res., 2015, 184(2), 151-160.
Sun, Y.; St Clair, D.K.; Xu, Y.; Crooks, P.A.; St Clair, W.H. A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. Cancer Res., 2010, 70(7), 2880-2890.

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Year: 2019
Page: [50 - 60]
Pages: 11
DOI: 10.2174/1874467211666181010154709
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