, Volume 25, Issue 4, pp 403–413 | Cite as

Melatonin as an anti-inflammatory agent in radiotherapy

  • M. Najafi
  • A. ShiraziEmail author
  • E. MotevaseliEmail author
  • A. H. Rezaeyan
  • A. Salajegheh
  • S. Rezapoor


Radiotherapy is one of the most relevant treatment options for cancer therapy with or without other treatment modalities including immunotherapy, surgery and chemotherapy. Exposure to heavy doses of ionizing radiation during radiotherapy results in short and long term side effects. It appears that many of these side effects are linked to inflammatory responses during treatment or after prolonged use. Inflammation is mediated by various genes and cytokines related to immune system responses caused by massive cell death following radiotherapy. This phenomenon is more obvious, particularly after exposure to clinical doses of radiotherapy. Inflammation is involved in the amplification of acute responses, genomic instability and also long term pathological changes in normal tissues. Moreover, inflammation attenuates responses of the tumor to radiotherapy through some mechanisms such as angiogenesis. Thus, the management of inflammation is one of the most interesting aims in cancer radiotherapy. Melatonin, known as a natural product in the body, has been of much interest for its anti-inflammatory properties. Some studies have proposed melatonin as a novel anti-inflammation agent. This literature review will concentrate on the anti-inflammatory properties of melatonin that may help the management of different inflammatory signaling pathways in both tumor and normal tissues.


Melatonin Inflammation Radiotherapy Oxidative stress Immune system 



Tehran University of Medical Sciences. Grant number 33480.

Compliance with ethical standards

Conflict of interest



  1. Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE (2003) Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol 45(1):55–75PubMedCrossRefGoogle Scholar
  2. Aghazadeh S et al (2007) Melatonin as a protective agent in spinal cord damage after gamma irradiation. Rep Prac Oncol Radiother 12(2):95–99CrossRefGoogle Scholar
  3. Andreassen CN, Grau C, Lindegaard JC (2003) Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol 13:62–72PubMedCrossRefGoogle Scholar
  4. Antolín ISAAC et al (1996) Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J 10(8):882–890PubMedGoogle Scholar
  5. Apetoh L et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059PubMedCrossRefGoogle Scholar
  6. Balamurugan K (2016) HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer 138(5):1058–1066PubMedCrossRefGoogle Scholar
  7. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217PubMedCrossRefGoogle Scholar
  8. Bangha E, Elsner P, Kistler GS (1996) Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study. Arch Dermatol Res 288(9):522–526PubMedCrossRefGoogle Scholar
  9. Barker HE et al (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15(7):409–425PubMedPubMedCentralCrossRefGoogle Scholar
  10. Baskar R et al (2012) Cancer and radiation therapy: current advances and future directions. Int J Med Sci 9(3):193–199PubMedPubMedCentralCrossRefGoogle Scholar
  11. Becciolini A et al (1997) The effects of irradiation at different times of the day on rat intestinal goblet cells. Cell Prolif 30(3–4):161–170PubMedCrossRefGoogle Scholar
  12. Ben-David MA et al (2015) Melatonin for Prevention of Breast Radiation Dermatitis: A Phase II, Prospective, Double-Blind Randomized Trial. Isr Med Assoc J IMAJ 18(3–4):188–192Google Scholar
  13. Bentzen SM (2006) Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 6(9):702–713PubMedCrossRefGoogle Scholar
  14. Bertuglia S, Marchiafava PL, Colantuoni A (1996) Melatonin prevents ischemia reperfusion injury in hamster cheek pouch microcirculation. Cardiovasc Res 31(6):947–952PubMedCrossRefGoogle Scholar
  15. Bhatia AL, Manda K (2004) Study on pre-treatment of melatonin against radiation-induced oxidative stress in mice. Environ Toxicol Pharmacol 18(1):13–20PubMedCrossRefGoogle Scholar
  16. Bordt SL et al (2001) N1E-115 mouse neuroblastoma cells express mt1 melatonin receptors and produce neurites in response to melatonin. Biochim Et Biophys Acta (BBA) Mol Cell Res 1499(3):257–264CrossRefGoogle Scholar
  17. Borek C (2004) Antioxidants and radiation therapy. J Nutr 134(11):3207S–3209SPubMedGoogle Scholar
  18. Bower JE et al (2011) Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? J Clin Oncol 29(26):3517–3522PubMedPubMedCentralCrossRefGoogle Scholar
  19. Burdelya LG et al (2008) An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320(5873):226–230PubMedPubMedCentralCrossRefGoogle Scholar
  20. Carrillo-Vico A et al (2003) Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci CMLS 60(10):2272–2278PubMedCrossRefGoogle Scholar
  21. Cayli SR et al (2004) Effect of combined treatment with melatonin and methylprednisolone on neurological recovery after experimental spinal cord injury. Eur Spine J 13(8):724–732PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cerutti P, Amstad P (1993) Inflammation and oxidative stress in carcinogenesis. Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury. Springer, New York, pp 387–390Google Scholar
  23. Chen LD et al (1995) Melatonin’s inhibitory effect on growth of ME-180 human cervical cancer cells is not related to intracellular glutathione concentrations. Cancer Lett 91(2):153–159PubMedCrossRefGoogle Scholar
  24. Choi YW et al (2004) Effects of Radiation Therapy on the Lung: Radiologic Appearances and Differential Diagnosis 1. Radiographics 24(4):985–997PubMedCrossRefGoogle Scholar
  25. Chun KS et al (2004) Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-κB. Carcinogenesis 25(3):445–454PubMedCrossRefGoogle Scholar
  26. Ciriaco M et al (2013) Corticosteroid-related central nervous system side effects. J Pharmacol Pharmacother 4(5):94CrossRefGoogle Scholar
  27. Colombo J et al (2016) Effects of melatonin on HIF-1alpha and VEGF expression and on the invasive properties of hepatocarcinoma cells. Oncol Lett 12(1):231–237PubMedPubMedCentralGoogle Scholar
  28. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266PubMedCrossRefGoogle Scholar
  29. Cos S et al (1996) Effects of melatonin on the proliferation and differentiation of human neuroblastoma cells in culture. Neurosci Lett 216(2):113–116PubMedCrossRefGoogle Scholar
  30. Delia P et al (2002) Prevention of radiation-induced diarrhea with the use of VSL# 3, a new high-potency probiotic preparation. Am J Gastroenterol 97(8):2150PubMedCrossRefGoogle Scholar
  31. Deng WG et al (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108(2):518–524PubMedPubMedCentralCrossRefGoogle Scholar
  32. Doctrow SR et al (2013) A synthetic superoxide dismutase/catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin. J Invest Dermatol 133(4):1088–1096PubMedCrossRefGoogle Scholar
  33. Dörr W, Hendry JH (2001) Consequential late effects in normal tissues. Radiother Oncol 61(3):223–231PubMedCrossRefGoogle Scholar
  34. Dragicevic N et al (2011) Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling. J Pineal Res 51(1):75–86PubMedCrossRefGoogle Scholar
  35. Dunst J et al (2000) Intermittent use of amifostine during postoperative radiochemotherapy and acute toxicity in rectal cancer patients. Strahlenther Onkol 176(9):416–421PubMedCrossRefGoogle Scholar
  36. Eiró N, Vizoso FJ (2012) Inflammation and cancer. World J Gastrointest Surg 4(3):62–72PubMedPubMedCentralCrossRefGoogle Scholar
  37. El-Missiry MA et al (2007) Ameliorative effect of melatonin against gamma-irradiation-induced oxidative stress and tissue injury. Ecotoxicol Environ Saf 66(2):278–286PubMedCrossRefGoogle Scholar
  38. Esrefoglu M et al (2006) Ultrastructural clues for the potent therapeutic effect of melatonin on aging skin in pinealectomized rats. Fundam Clin Pharmacol 20(6):605–611PubMedCrossRefGoogle Scholar
  39. Fischer TW et al (2008) Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair. Exp Dermatol 17(9):713–730PubMedCrossRefGoogle Scholar
  40. Forrest LM et al (2003) Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer 89(6):1028–1030PubMedPubMedCentralCrossRefGoogle Scholar
  41. Foulkes NS, Borjigin J, Snyder SH (1997) Rhythmic transcription: the molecular basis of circadian melatonin synthesis. Trends Neurosci 20(10):487–492PubMedCrossRefGoogle Scholar
  42. Georgakilas AG (2015) Role of the immune system and inflammation in ionizing radiation effects. Cancer Lett 368(2):154PubMedCrossRefGoogle Scholar
  43. Gilad E et al (1998) Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFκB activation. FASEB J 12(9):685–693PubMedGoogle Scholar
  44. Gilkes DM, Semenza GL (2013) Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol 9(11):1623–1636PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gitto E et al (2001) Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrrioxamine (desferoxamine) in rat liver homogenates. J Pharm Pharmacol 53(10):1393–1401PubMedCrossRefGoogle Scholar
  46. Guney Y et al (2007) Melatonin prevents inflammation and oxidative stress caused by abdominopelvic and total body irradiation of rat small intestine. Braz J Med Biol Res 40(10):1305–1314PubMedCrossRefGoogle Scholar
  47. Gupta SC et al (2010) Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 29(3):405–434PubMedPubMedCentralCrossRefGoogle Scholar
  48. Haddadi G et al (2013) Radioprotective effect of melatonin on the cervical spinal cord in irradiated rats. Cell J (Yakhteh) 14(4):246Google Scholar
  49. Hakem R (2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27(4):589–605PubMedPubMedCentralCrossRefGoogle Scholar
  50. Halin C, Detmar M (2008) Inflammation, angiogenesis, and lymphangiogenesis. Methods Enzymol 445:1–25PubMedCrossRefGoogle Scholar
  51. Hekim N et al (2015) Radiation triggering immune response and inflammation. Cancer Lett 368(2):156–163PubMedCrossRefGoogle Scholar
  52. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027PubMedCrossRefGoogle Scholar
  53. Hill SM et al (2015) Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer 22(3):R183–R204PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hong JH et al (1995) Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys 33(3):619–626PubMedCrossRefGoogle Scholar
  55. Hovdenak N, Fajardo LF, Hauer-Jensen M (2000) Acute radiation proctitis: a sequential clinicopathologic study during pelvic radiotherapy. Int J Radiat Oncol Biol Phys 48(4):1111–1117PubMedCrossRefGoogle Scholar
  56. Hovdenak N et al (2003) Profiles and time course of acute radiation toxicity symptoms during conformal radiotherapy for cancer of the prostate. Acta Oncol 42(7):741–748PubMedCrossRefGoogle Scholar
  57. Hu ZP et al (2013) Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR4/NF-κB system in high-fat-fed rabbits. J Pineal Res 55(4):388–398PubMedGoogle Scholar
  58. Huether G (1993) The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 49(8):665–670PubMedCrossRefGoogle Scholar
  59. Hussein MR et al (2005) Ultrastructural evaluation of the radioprotective effects of melatonin against X-ray-induced skin damage in Albino rats. Int J Exp Pathol 86(1):45–55PubMedPubMedCentralCrossRefGoogle Scholar
  60. Hussein MR et al (2008) Melatonin and roentgen irradiation-induced acute radiation enteritis in Albino rats: an animal model. Cell Biol Int 32(11):1353–1361PubMedCrossRefGoogle Scholar
  61. Inoue A et al (2001) Radiation pneumonitis in lung cancer patients: a retrospective study of risk factors and the long-term prognosis. Int J Radiat Oncol Biol Phys 49(3):649–655PubMedCrossRefGoogle Scholar
  62. Jang SS et al (2013) Melatonin reduces X-ray radiation-induced lung injury in mice by modulating oxidative stress and cytokine expression. Int J Radiat Biol 89(2):97–105PubMedCrossRefGoogle Scholar
  63. Jardim-Perassi BV et al (2016) Melatonin regulates angiogenic factors under hypoxia in breast cancer cell lines. Anticancer Agents Med Chem 16(3):347–358PubMedCrossRefGoogle Scholar
  64. Jung JI et al (2004) Thoracic Manifestations of Breast Cancer and Its Therapy 1. Radiographics 24(5):1269–1285PubMedCrossRefGoogle Scholar
  65. Kaur P, Asea A (2012) Radiation-induced effects and the immune system in cancer. Front Oncol 2:191PubMedPubMedCentralCrossRefGoogle Scholar
  66. Kaya H et al (1999) The effect of melatonin on lipid peroxidation during radiotherapy in female rats. Strahlenther Onkol 175(6):285–288PubMedCrossRefGoogle Scholar
  67. Kim BC et al (2001) Melatonin reduces X-ray irradiation-induced oxidative damages in cultured human skin fibroblasts. J Dermatol Sci 26(3):194–200PubMedCrossRefGoogle Scholar
  68. Koc M et al (2003) Melatonin protects rat liver against irradiation-induced oxidative injury. J Radiat Res 44(3):211–215PubMedCrossRefGoogle Scholar
  69. Komaki R et al (2004) Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non–small-cell lung cancer: Report of a randomized comparative trial. Int J Radiat Oncol Biol Phys 58(5):1369–1377PubMedCrossRefGoogle Scholar
  70. Kotler M et al (1998) Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 24(2):83–89PubMedCrossRefGoogle Scholar
  71. Lan F et al (2014) Serum toll-like receptors are potential biomarkers of radiation pneumonia in locally advanced NSCLC. Int J Clin Exp Pathol 7(11):8087–8095PubMedPubMedCentralGoogle Scholar
  72. Lauber K et al (2012) Dying cell clearance and its impact on the outcome of tumor radiotherapy. Front Oncol 2:116PubMedPubMedCentralCrossRefGoogle Scholar
  73. Li F, Sethi G (2010) Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Et Biophys Acta (BBA) Rev Cancer 2:167–180CrossRefGoogle Scholar
  74. Lin R et al (2015) Chronic inflammation-related DNA damage response: a driving force of gastric cardia carcinogenesis. Oncotarget 6(5):2856PubMedCrossRefGoogle Scholar
  75. Lissoni P et al (2001) Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett 22(1):45–47PubMedGoogle Scholar
  76. Lorimore SA et al (2001) Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Oncogene 20(48):7085–7095PubMedCrossRefGoogle Scholar
  77. Lugade AA et al (2008) Radiation-induced IFN-γ production within the tumor microenvironment influences antitumor immunity. J Immunol 180(5):3132–3139PubMedCrossRefGoogle Scholar
  78. Mahal HS, Sharma HS, Mukherjee T (1999) Antioxidant properties of melatonin: a pulse radiolysis study. Free Radic Biol Med 26(5):557–565PubMedCrossRefGoogle Scholar
  79. Marozik P et al (2007) Bystander effects induced by serum from survivors of the Chernobyl accident. Exp Hematol 35(4):55–63PubMedCrossRefGoogle Scholar
  80. Marseglia L et al (2014) Melatonin and atopy: role in atopic dermatitis and asthma. Int J Mol Sci 15(8):13482–13493PubMedPubMedCentralCrossRefGoogle Scholar
  81. Matuszak Z, Reszka KJ, Chignell CF (1997) Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic Biol Med 23(3):367–372PubMedCrossRefGoogle Scholar
  82. Mayo JC et al (2002) Melatonin regulation of antioxidant enzyme gene expression. Cell Mol Life Sci CMLS 59(10):1706–1713PubMedCrossRefGoogle Scholar
  83. Mayo JC et al (2005) Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol 165(1–2):139–149PubMedCrossRefGoogle Scholar
  84. Meacham LR, Sklar CA, Li S, Liu Q, Gimpel N, Yasui Y, Whitton JA, Stovall M, Robison LL, Oeffinger KC (2009) Diabetes mellitus in long-term survivors of childhood cancer. Arch Inter Med 169 (15):1381CrossRefGoogle Scholar
  85. Mehta V (2005) Radiation pneumonitis and pulmonary fibrosis in non–small-cell lung cancer: Pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys 63(1):5–24PubMedCrossRefGoogle Scholar
  86. Meira LB et al (2008) DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Investig 118(7):2516–2525PubMedPubMedCentralGoogle Scholar
  87. Mihandoost E et al (2014) Can melatonin help us in radiation oncology treatments? Biomed Res Int 2014:578137. doi: 10.1155/2014/578137 PubMedPubMedCentralCrossRefGoogle Scholar
  88. Min D et al (2002) Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99(12):4592–4600PubMedCrossRefGoogle Scholar
  89. Mohan N et al (1995) The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-kappa B. Biochem Mol Biol Int 37(6):1063–1070PubMedGoogle Scholar
  90. Mohseni M et al (2012) Melatonin may play a role in modulation of bax and bcl-2 expression levels to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis. Mutat Res Fundam Mol Mech Mutagen 738–739:19–27CrossRefGoogle Scholar
  91. Monobe M et al (2005) Protective effects of melatonin on gamma-ray induced intestinal damage. Int J Radiat Biol 81(11):855–860PubMedCrossRefGoogle Scholar
  92. Movsas B et al (1997) Pulmonary radiation injury. Chest J 111(4):1061–1076CrossRefGoogle Scholar
  93. Mukherjee D et al (2014) Responses to ionizing radiation mediated by inflammatory mechanisms. J Pathol 232(3):289–299PubMedCrossRefGoogle Scholar
  94. Multhoff G, Radons J (2012) Radiation, inflammation, and immune responses in cancer. Front Oncol 2:58PubMedPubMedCentralGoogle Scholar
  95. Najafi M et al (2016) Radiation-induced oxidative stress at out-of-field lung tissues after pelvis irradiation in rats. Cell J (Yakhteh) 18(3):340Google Scholar
  96. Nathan C (2003) Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J Clin Investig 111(6):769–778PubMedPubMedCentralCrossRefGoogle Scholar
  97. Newhauser WD, Durante M (2011) Assessing the risk of second malignancies after modern radiotherapy. Nat Rev Cancer 11(6):438–448PubMedPubMedCentralCrossRefGoogle Scholar
  98. Nooshinfar E et al (2016) Melatonin, an inhibitory agent in breast cancer. Breast Cancer 24:1–10Google Scholar
  99. Ohnishi S et al (2013) DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev 2013:387014. doi: 10.1155/2013/387014 PubMedPubMedCentralCrossRefGoogle Scholar
  100. Fardid R, Salajegheh A, Mosleh-Shirazi MA, Sharifzadeh S, Okhovat MA, Najafi M, Rezaeyan A, Abaszadeh A (2017) Melatonin ameliorates the production of COX-2, iNOS, and the formation of 8-OHdG in non-targeted lung tissue after pelvic irradiation. Cell J 19(2):324–331PubMedPubMedCentralGoogle Scholar
  101. Okatani Y et al (2001) Melatonin stimulates glutathione peroxidase activity in human chorion. J Pineal Res 30(4):199–205PubMedCrossRefGoogle Scholar
  102. Onal C et al (2011) Protective effects of melatonin and octreotide against radiation-induced intestinal injury. Dig Dis Sci 56(2):359–367PubMedCrossRefGoogle Scholar
  103. Ong ZY et al (2010) Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis. Radiat Oncol 5(1):1CrossRefGoogle Scholar
  104. Ortiz F et al (2015) Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res 58(1):34–49PubMedCrossRefGoogle Scholar
  105. Pablos MI et al (1995) Melatonin stimulates the activity of the detoxifying enzyme glutathione peroxidase in several tissues of chicks. J Pineal Res 19(3):111–115PubMedCrossRefGoogle Scholar
  106. Pablos MI et al (1998) Rhythms of glutathione peroxidase and glutathione reductase in brain of chick and their inhibition by light. Neurochem Int 32(1):69–75PubMedCrossRefGoogle Scholar
  107. Peddi PF, Shatsky RA, Hurvitz SA (2014) Noninfectious pneumonitis with the use of mTOR inhibitors in breast cancer. Cancer Treat Rev 40(2):320–326PubMedCrossRefGoogle Scholar
  108. Perez-Sala D, Lamas S (2001) Regulation of cyclooxygenase-2 expression by nitric oxide in cells. Antioxid Redox Signal 3(2):231–248PubMedCrossRefGoogle Scholar
  109. Philip B et al (2013) HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 34(8):1699–1707PubMedCrossRefGoogle Scholar
  110. Reiter RJ, Tan DX, Burkhardt S (2002) Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech Ageing Dev 123(8):1007–1019PubMedCrossRefGoogle Scholar
  111. Reits EA et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203(5):1259–1271PubMedPubMedCentralCrossRefGoogle Scholar
  112. Rezaeyan A et al (2016a) Evaluating radioprotective effect of hesperidin on acute radiation damage in the lung tissue of rats. J Biomed Phys Eng 6(3):165–174PubMedPubMedCentralGoogle Scholar
  113. Rezaeyan A et al (2016b) Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue. J Med Phys Assoc Med Phys India 41(3):182Google Scholar
  114. Rezvani M (2003) Treatment of radiation-induced normal tissue lesions. Iran J Radiat Res 1(2):63–78Google Scholar
  115. Roach MIII et al (1995) Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol 13(10):2606–2612PubMedCrossRefGoogle Scholar
  116. Robbins MEC, Zhao W (2004) Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol 80(4):251–259PubMedCrossRefGoogle Scholar
  117. Rödel F et al (2012) Immunomodulatory properties and molecular effects in inflammatory diseases of low-dose X-irradiation. Front Oncol 2:120PubMedPubMedCentralCrossRefGoogle Scholar
  118. Rodriguez C et al (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36(1):1–9PubMedCrossRefGoogle Scholar
  119. Rosiello RA, Merrill WW (1990) Radiation-induced lung injury. Clin Chest Med 11(1):65–71PubMedGoogle Scholar
  120. Roth JA, Rabin R, Agnello K (1997) Melatonin suppression of PC12 cell growth and death. Brain Res 768(1–2):63–70PubMedCrossRefGoogle Scholar
  121. Rubio S et al (2007) Inhibition of proliferation and induction of apoptosis by melatonin in human myeloid HL-60 cells. J Pineal Res 42(2):131–138PubMedCrossRefGoogle Scholar
  122. Sainz RM et al (2003a) Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60(7):1407–1426PubMedCrossRefGoogle Scholar
  123. Sainz RM et al (2003b) Antioxidant activity of melatonin in Chinese hamster ovarian cells: changes in cellular proliferation and differentiation. Biochem Biophys Res Commun 302(3):625–634PubMedCrossRefGoogle Scholar
  124. Schaue D, Kachikwu EL, McBride WH (2012) Cytokines in radiobiological responses: a review. Radiat Res 178(6):505–523PubMedPubMedCentralCrossRefGoogle Scholar
  125. Sekine I et al (2006) Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients. Radiother Oncol 80(1):93–97PubMedCrossRefGoogle Scholar
  126. Şener G et al (2003) Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats. Life Sci 74(5):563–572PubMedCrossRefGoogle Scholar
  127. Serin M et al (2007) The histopathological evaluation of the effectiveness of melatonin as a protectant against acute lung injury induced by radiation therapy in a rat model. Int J Radiat Biol 83(3):187–193PubMedCrossRefGoogle Scholar
  128. Sewerynek E et al (1995) Oxidative damage in the liver induced by ischemia-reperfusion: protection by melatonin. Hepatogastroenterology 43(10):898–905Google Scholar
  129. Shakhov AN et al (2012) Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2). PLoS One 7(3):e33044PubMedPubMedCentralCrossRefGoogle Scholar
  130. Shiao SL, Coussens LM (2010) The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplas 15(4):411–421CrossRefGoogle Scholar
  131. Shirazi A (2011) Radioprotective effect of melatonin in reducing oxidative stress in rat lenses. Radiother Oncol 98:S21CrossRefGoogle Scholar
  132. Shirazi A, Mahdavi SR, Trott KR (2004) Radiation myelopathy: a radiobiological review. Rep Pract Oncol Radiother 9(4):119–127CrossRefGoogle Scholar
  133. Shirazi A et al (2005) Short-term changes in prostacyclin secretory profile of irradiated rat cervical spinal cord. Prostaglandins Leukot Essent Fat Acids 72(5):373–378CrossRefGoogle Scholar
  134. Shirazi A et al (2010) Evaluation of melatonin for modulation of apoptosis-related genes in irradiated cervical spinal cord. Int J Low Radiat 7(6):436–445CrossRefGoogle Scholar
  135. Shirazi A et al (2013a) Radio-protective effects of melatonin against irradiation-induced oxidative damage in rat peripheral blood. Phys Med 29(1):65–74PubMedCrossRefGoogle Scholar
  136. Shirazi A et al (2013b) Evaluation of radio-protective effect of melatonin on whole body irradiation induced liver tissue damage. Cell 14(4):294–297Google Scholar
  137. Slominski A, Pruski D (1993) Melatonin inhibits proliferation and melanogenesis in rodent melanoma cells. Exp Cell Res 206(2):189–194PubMedCrossRefGoogle Scholar
  138. Slominski A et al (2008) Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab 19(1):17–24PubMedCrossRefGoogle Scholar
  139. Somosy Z et al (2002) Morphological aspects of ionizing radiation response of small intestine. Micron 33(2):167–178PubMedCrossRefGoogle Scholar
  140. Sprung CN et al (2015) Immunological markers that predict radiation toxicity. Cancer Lett 368(2):191–197PubMedCrossRefGoogle Scholar
  141. Stasica P, Ulanski P, Rosiak JM (1998) Melatonin as a hydroxyl radical scavenger. J Pineal Res 25(1):65–66PubMedCrossRefGoogle Scholar
  142. Tan DX et al (2003) Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical. J Pineal Res 34(4):249–259PubMedCrossRefGoogle Scholar
  143. Tan DX et al (2007) One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42(1):28–42PubMedCrossRefGoogle Scholar
  144. Tan DX et al (2013) Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J Pineal Res 54(2):127–138PubMedCrossRefGoogle Scholar
  145. Tan DX et al (2015) Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism. Molecules 20(10):18886–18906PubMedCrossRefGoogle Scholar
  146. Tavassoli A, Ghasemi D (2015) Radioprotective effect of melatonin on radiation-induced lung injury and lipid peroxidation in rats. Cell J 17(1):111PubMedPubMedCentralGoogle Scholar
  147. Tsoutsou PG, Koukourakis MI (2006) Radiation pneumonitis and fibrosis: mechanisms underlying its pathogenesis and implications for future research. Int J Radiat Oncol Biol Phys 66(5):1281–1293PubMedCrossRefGoogle Scholar
  148. Wang Y et al (2004) Activation of nuclear factor κB in vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res 64(17):6240–6246PubMedCrossRefGoogle Scholar
  149. Yang QH et al (2007) Antiproliferative effects of melatonin on the growth of rat pituitary prolactin-secreting tumor cells in vitro. J Pineal Res 42(2):172–179PubMedCrossRefGoogle Scholar
  150. Yi C et al (2014) Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways. PLoS One 9(7):e99943PubMedPubMedCentralCrossRefGoogle Scholar
  151. Yilmaz S, Yilmaz E (2006) Effects of melatonin and vitamin E on oxidative–antioxidative status in rats exposed to irradiation. Toxicology 222(1):1–7PubMedCrossRefGoogle Scholar
  152. Ying SW, Niles LP, Crocker C (1993) Human malignant melanoma cells express high-affinity receptors for melatonin: antiproliferative effects of melatonin and 6-chloromelatonin. Eur J Pharmacol Mol Pharmacol 246(2):89–96CrossRefGoogle Scholar
  153. Zhang S et al (2013) Melatonin inhibits cell growth and migration, but promotes apoptosis in gastric cancer cell line, SGC7901. Biotech Histochem 88(6):281–289PubMedCrossRefGoogle Scholar
  154. Zhao W, Robbins MEC (2009) Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem 16(2):130–143PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Department of Medical Physics and Biomedical Engineering, Faculty of MedicineTehran University of Medical SciencesTehranIran
  2. 2.Department of Molecular Medicine, School of Advanced Technologies in MedicineTehran University of Medical SciencesTehranIran
  3. 3.Department of Medical Physics, Faculty of MedicineIran University of Medical SciencesTehranIran
  4. 4.Department of Radiology, Faculty of ParamedicalShiraz University of Medical SciencesShirazIran
  5. 5.Department of Radiology, Faculty of ParamedicalTehran University of Medical SciencesTehranIran

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