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The melatonin immunomodulatory actions in radiotherapy

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Abstract

Radiotherapy has a key role in cancer treatment in more than half of patients with cancer. The management of severe side effects of this treatment modality is a limiting factor to appropriate treatment. Immune system responses play a pivotal role in many of the early and late side effects of radiation. Moreover, immune cells have a significant role in tumor response to radiotherapy, such as angiogenesis and tumor growth. Melatonin as a potent antioxidant has shown appropriate immune regulatory properties that may ameliorate toxicity induced by radiation in various organs. These effects are mediated through various modulatory effects of melatonin in different levels of tissue reaction to ionizing radiation. The effects on the DNA repair system, antioxidant enzymes, immune cells, cytokines secretion, transcription factors, and protein kinases are most important. Moreover, anti-cancer properties of melatonin may increase the therapeutic ratio of radiotherapy. Clinical applications of this agent for the management of malignancies such as breast cancer have shown promising results. It seems anti-proliferative, anti-angiogenesis, and stimulation or suppression of some immune cell responses are the main anti-tumor effects of melatonin that may help to improve response of the tumor to radiotherapy. In this review, the effects of melatonin on the modulation of immune responses in both normal and tumor tissues will be discussed.

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References

  • Amundson SA (2008) Functional genomics and a new era in radiation biology and oncology. Bioscience 58(6):491–500

    Article  PubMed  PubMed Central  Google Scholar 

  • Aydogan S, Yerer MB, Goktas A (2006) Melatonin and nitric oxide. J Endocrinol Investig 29(3):281–287

    Article  CAS  Google Scholar 

  • Behr TM, Sgouros G, Stabin MG, Béhé M, Angerstein C, Blumenthal RD et al (1999) Studies on the red marrow dosimetry in radioimmunotherapy: an experimental investigation of factors influencing the radiation-induced myelotoxicity in therapy with β-, Auger/conversion electron-, or α-emitters. Clin Cancer Res 5(10):3031s–3043s

    CAS  PubMed  Google Scholar 

  • Bentzen SM (2006) Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 6(9):702–713

    Article  CAS  PubMed  Google Scholar 

  • Bondy SC, Lahiri DK, Perreau VM, Sharman KZ, Campbell A, Zhou J et al (2004) Retardation of brain aging by chronic treatment with melatonin. Ann N Y Acad Sci 1035(1):197–215

    Article  CAS  PubMed  Google Scholar 

  • Bower JE, Ganz PA, Aziz N, Fahey JL (2002) Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 64(4):604–611

    Article  PubMed  Google Scholar 

  • Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S et al (2009) Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clin Cancer Res 15(17):5534–5540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brush J, Lipnick SL, Phillips T, Sitko J, McDonald JT, McBride WH (eds) (2007) Molecular mechanisms of late normal tissue injury. Seminars in radiation oncology. Elsevier

  • Caballero B, Vega‐Naredo I, Sierra V, Huidobro‐Fernández C, Soria‐Valles C, Gonzalo‐Calvo D et al (2009) Melatonin alters cell death processes in response to age‐related oxidative stress in the brain of senescence‐accelerated mice. J Pineal Res 46(1):106–114

    Article  CAS  PubMed  Google Scholar 

  • Cagnoli CM, Atabay C, Kharlamova E, Manev H (1995) Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res 18(4):222–226

    Article  CAS  PubMed  Google Scholar 

  • Cakmak Karaer I, Simsek G, Yildiz A, Vardi N, Polat A, Tanbek K et al (2016) Melatonin’s protective effect on the salivary gland against ionized radiation damage in rats. J Oral Pathol Med 45(6):444–449

    Article  CAS  PubMed  Google Scholar 

  • Calveley VL, Khan MA, Yeung IW, Vandyk J, Hill RP (2005) Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation. Int J Radiat Biol 81(12):887–899

    Article  CAS  PubMed  Google Scholar 

  • Canyilmaz E, Uslu GH, Bahat Z, Kandaz M, Mungan S, Haciislamoglu E et al (2016) Comparison of the effects of melatonin and genistein on radiation-induced nephrotoxicity: Results of an experimental study. Biomed Rep 4(1):45–50

    PubMed  Google Scholar 

  • Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM et al (2006) The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs 7(5):423

    CAS  PubMed  Google Scholar 

  • Chávez E, Reyes‐Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P et al (2008) Resveratrol prevents fibrosis, NF‐κB activation and TGF‐β increases induced by chronic CCl4 treatment in rats. J Appl Toxicol 28(1):35–43

    Article  PubMed  CAS  Google Scholar 

  • Chetsawang B, Putthaprasart C, Phansuwan-Pujito P, Govitrapong P (2006) Melatonin protects against hydrogen peroxide-induced cell death signaling in SH-SY5Y cultured cells: involvement of nuclear factor kappa B, Bax and Bcl-2. J Pineal Res 41(2):116–123

    Article  CAS  PubMed  Google Scholar 

  • Cho SY, Lee HJ, Jeong SJ, Lee HJ, Kim HS, Chen CY et al (2011) Sphingosine kinase 1 pathway is involved in melatonin‐induced HIF‐1α inactivation in hypoxic PC‐3 prostate cancer cells. J Pineal Res 51(1):87–93

    Article  CAS  PubMed  Google Scholar 

  • Choi YW, Munden RF, Erasmus JJ, Joo Park K, Chung WK, Jeon SC et al (2004) Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis 1. Radiographics 24(4):985–997

    Article  PubMed  Google Scholar 

  • Choi EY, Jin JY, Lee JY, Choi JI, Choi IS, Kim SJ (2011) Melatonin inhibits Prevotella intermedia lipopolysaccharide‐induced production of nitric oxide and interleukin‐6 in murine macrophages by suppressing NF‐κB and STAT1 activity. J Pineal Res 50(2):197–206

    CAS  PubMed  Google Scholar 

  • Christopher FL, Dussault I, Miller SC (1991) Population dynamics of natural killer cells in the spleen and bone marrow of normal and leukemic mice during in vivo exposure to interleukin-2. Immunobiology 184(1):37–52

    Article  CAS  PubMed  Google Scholar 

  • Cos S, Blask DE (1994) Melatonin modulates growth factor activity in MCF‐7 human breast cancer cells. J Pineal Res 17(1):25–32

    Article  CAS  PubMed  Google Scholar 

  • Cucina A, Proietti S, D’Anselmi F, Coluccia P, Dinicola S, Frati L et al (2009) Evidence for a biphasic apoptotic pathway induced by melatonin in MCF‐7 breast cancer cells. J Pineal Res 46(2):172–180

    Article  CAS  PubMed  Google Scholar 

  • Currier NL, Miller SC (2001) Echinacea purpurea and melatonin augment natural-killer cells in leukemic mice and prolong life span. J Altern Complement Med (New York, NY) 7(3):241–251

    Article  CAS  Google Scholar 

  • Currier NL, Sun L-Y, Miller SC (2000) Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity. J Neuroimmunol 104(2):101–108

    Article  CAS  PubMed  Google Scholar 

  • Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabo C (1997) Protective effect of melatonin in carrageenan‐induced models of local inflammation: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J Pineal Res 23(2):106–116

    Article  CAS  PubMed  Google Scholar 

  • Cuzzocrea S, Costantino G, Mazzon E, Caputi AP (1999) Regulation of prostaglandin production in carrageenan‐induced pleurisy melatonin. J Pineal Res 27(1):9–14

    Article  CAS  PubMed  Google Scholar 

  • Deng W-G, Tang S-T, Tseng H-P, Wu KK (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108(2):518–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Bella G, Mascia F, Gualano L, Di Bella L (2013) Melatonin anticancer effects: review. Int J Mol Sci 14(2):2410–2430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Di Maggio FM, Minafra L, Forte GI, Cammarata FP, Lio D, Messa C et al (2015) Portrait of inflammatory response to ionizing radiation treatment. J Inflamm 12(1):14

    Article  CAS  Google Scholar 

  • Dragicevic N, Copes N, O’Neal‐Moffitt G, Jin J, Buzzeo R, Mamcarz M 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):75–86

    Article  CAS  PubMed  Google Scholar 

  • Emerit I, Oganesian N, Sarkisian T, Arutyunyan R, Pogosian A, Asrian K et al (1995) Clastogenic factors in the plasma of Chernobyl accident recovery workers: anticlastogenic effect of Ginkgo biloba extract. Radiat Res 144(2):198–205

    Article  CAS  PubMed  Google Scholar 

  • 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):324-331. doi:10.22074/cellj.2016.3857

  • García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC et al (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J 29(9):3863–3875

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Maurino S, Gonzalez-Haba MG, Calvo JR, Rafii-El-Idrissi M, Sanchez-Margalet V, Goberna R et al (1997) Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol 159(2):574–581

    CAS  PubMed  Google Scholar 

  • García‐Mauriño S, Pozo D, Calvo JR, Guerrero JM (2000) Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines. J Pineal Res 29(3):129–137

    Article  PubMed  Google Scholar 

  • Garcı́a-Pergañeda A, Guerrero JM, Rafii-El-Idrissi M, Romero MP, Pozo D, Calvo JR (1999) Characterization of membrane melatonin receptor in mouse peritoneal macrophages: inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein. J Neuroimmunol 95(1):85–94

    Article  PubMed  Google Scholar 

  • Golden EB, Apetoh L (eds) (2015) Radiotherapy and immunogenic cell death. Seminars in radiation oncology. Elsevier

  • Golden E, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC (2012) The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2:88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green DR, Ferguson T, Zitvogel L, Kroemer G (2009) Immunogenic and tolerogenic cell death. Nat Rev Immunol 9(5):353–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gürses İ, Özeren M, Serin M, Yücel N, Erkal HŞ (2014) Histopathological evaluation of melatonin as a protective agent in heart injury induced by radiation in a rat model. Pathol Res Pract 210(12):863–871

    Article  PubMed  CAS  Google Scholar 

  • Haddadi GH, Shirazi AR, Sepehrizadeh Z, Mahdavi SR, Haddadi M (2013) Radioprotective effect of melatonin on the cervical spinal cord in irradiated rats. Cell J 14(4):246–253

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harris JW, Phillips TL (1971) Radiobiological and biochemical studies of thiophosphate radioprotective compounds related to cysteamine. Radiat Res 46(2):362–379

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto S, Shirato H, Hosokawa M, Nishioka T, Kuramitsu Y, Matushita K et al (1999) The suppression of metastases and the change in host immune response after low-dose total-body irradiation in tumor-bearing rats. Radiat Res 151(6):717–724

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Morishita Y, Kubo Y, Kusunoki Y, Hayashi I, Kasagi F et al (2005) Long-term effects of radiation dose on inflammatory markers in atomic bomb survivors. Am J Med 118(1):83–86

    Article  PubMed  Google Scholar 

  • Haddadi GH, Rezaeyan A, Mosleh-Shirazi MA, Hosseinzadeh M, Fardid R, Najafi M, et al (2017) Hesperidin as radioprotector against radiation-induced lung damage in rat: A histopathological study. J Med Phys 42:25–32

  • Heylmann D, Rödel F, Kindler T, Kaina B (2014) Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. Biochim Biophys Acta Rev Cancer 1846(1):121–129

    Article  CAS  Google Scholar 

  • Hong Y, Won J, Lee Y, Lee S, Park K, Chang KT et al (2014) Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. J Pineal Res 56(3):264–274

    Article  CAS  PubMed  Google Scholar 

  • Jang SS, Kim HG, Lee JS, Han JM, Park HJ, Huh GJ 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):97–105

    Article  CAS  PubMed  Google Scholar 

  • Jardim BV, Ferreira LC, Borin TF, Moschetta MG, Gelaleti GB, Lopes JR et al (eds) (2013) Evaluation of the anti-angiogenic action of melatonin in breast cancer. BMC Proceedings, BioMed Central

  • Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander AS et al (2014) Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One 9(1):e85311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Joo SS, Yoo YM (2009) Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res 47(1):8–14

    Article  CAS  PubMed  Google Scholar 

  • Kang JW, Lee SM (2012) Melatonin inhibits type 1 interferon signaling of toll‐like receptor 4 via heme oxygenase‐1 induction in hepatic ischemia/reperfusion. J Pineal Res 53(1):67–76

    Article  CAS  PubMed  Google Scholar 

  • Karslioğlu I, Ertekin MV, Taysi S, Koçer I, Sezen O, Gepdiremen A et al (2005) Radioprotective effects of melatonin on radiation-induced cataract. J Radiat Res 46(2):277–282

    Article  PubMed  Google Scholar 

  • Kaur C, Ling EA (1999) Effects of melatonin on macrophages/microglia in postnatal rat brain. J Pineal Res 26(3):158–168

    Article  CAS  PubMed  Google Scholar 

  • Kiefer W, Dannhardt G (2002) COX-2 inhibition and the control of pain. Curr Opin Investig Drugs (London, England: 2000) 3(9):1348–1358

    CAS  Google Scholar 

  • Kireev RA, Tresguerres AC, Castillo C, Salazar V, Ariznavarreta C, Vara E et al (2007) Effect of exogenous administration of melatonin and growth hormone on pro‐antioxidant functions of the liver in aging male rats. J Pineal Res 42(1):64–70

    Article  CAS  PubMed  Google Scholar 

  • Kleszczyński K, Zillikens D, Fischer TW (2016) Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2‐related factor 2 resulting in activation of phase‐2 antioxidant enzymes (γ‐GCS, HO‐1, NQO1) in ultraviolet radiation‐treated normal human epidermal keratinocytes (NHEK). J Pineal Res 61(2):187–197

    Article  PubMed  CAS  Google Scholar 

  • Kohchi C, Inagawa H, Nishizawa T, Soma G-I (2009) ROS and innate immunity. Anticancer Res 29(3):817–821

    CAS  PubMed  Google Scholar 

  • Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan D-X (2009) Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med 15(1–2):43–50

    CAS  PubMed  Google Scholar 

  • Kotler M, Rodríguez C, Sáinz RM, Antolin I, Menéndez‐Peláez A (1998) Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 24(2):83–89

    Article  CAS  PubMed  Google Scholar 

  • Kusunoki Y, Hayashi T (2008) Long-lasting alterations of the immune system by ionizing radiation exposure: implications for disease development among atomic bomb survivors. Int J Radiat Biol 84(1):1–14

    Article  CAS  PubMed  Google Scholar 

  • Kusunoki Y, Yamaoka M, Kubo Y, Hayashi T, Kasagi F, Douple EB et al (2010) T-cell immunosenescence and inflammatory response in atomic bomb survivors. Radiat Res 174(6b):870–876

    Article  CAS  PubMed  Google Scholar 

  • Leach JK, Van Tuyle G, Lin P-S, Schmidt-Ullrich R, Mikkelsen RB (2001) Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res 61(10):3894–3901

    CAS  PubMed  Google Scholar 

  • León J, Casado J, Jiménez Ruiz SM, Zurita MS, González‐Puga C, Rejón JD et al (2014) Melatonin reduces endothelin‐1 expression and secretion in colon cancer cells through the inactivation of FoxO‐1 and NF‐κβ. J Pineal Res 56(4):415–426

    Article  PubMed  CAS  Google Scholar 

  • Lezoualc’h F, Sparapani M, Behl C (1998) N‐acetyl‐serotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF‐κB. J Pineal Res 24(3):168–178

    Article  PubMed  Google Scholar 

  • Li W, Fan M, Chen Y, Zhao Q, Song C, Yan Y et al (2015) Melatonin induces cell apoptosis in AGS cells through the activation of JNK and P38 MAPK and the suppression of nuclear factor-kappa B: a novel therapeutic implication for gastric cancer. Cell Physiol Biochem 37(6):2323–2338

    Article  CAS  PubMed  Google Scholar 

  • Linard C, Marquette C, Mathieu J, Pennequin A, Clarençon D, Mathé D (2004) Acute induction of inflammatory cytokine expression after γ-irradiation in the rat: effect of an NF-κB inhibitor. Int J Radiat Oncol Biol Phys 58(2):427–434

    Article  CAS  PubMed  Google Scholar 

  • Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ (2001) Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinol Lett 22(1):45–48

    CAS  PubMed  Google Scholar 

  • Liu H, Xu L, Wei JE, Xie MR, Wang SE, Zhou RX (2011) Role of CD4+ CD25+ regulatory T cells in melatonin‐mediated inhibition of murine gastric cancer cell growth in vivo and in vitro. Anat Rec 294(5):781–788

    Article  CAS  Google Scholar 

  • Lorimore SA, Coates PJ, Scobie GE, Milne G, Wright EG (2001) Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Oncogene 20(48):7085–7095

    Article  CAS  PubMed  Google Scholar 

  • Luchetti F, Betti M, Canonico B, Arcangeletti M, Ferri P, Galli F et al (2009) ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells. Free Radic Biol Med 46(3):339–351

    Article  CAS  PubMed  Google Scholar 

  • Maestroni GJ (1995) T‐Helper‐2 lymphocytes as a peripheral target of melatonin. J Pineal Res 18(2):84–89

    Article  CAS  PubMed  Google Scholar 

  • Manchester LC, Coto‐Montes A, Boga JA, Andersen LPH, Zhou Z, Galano A et al (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 59(4):403–419

    Article  CAS  PubMed  Google Scholar 

  • Mayo JC, Sainz RM, Tan D-X, Hardeland R, Leon J, Rodriguez C 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):139–149

    Article  CAS  PubMed  Google Scholar 

  • Meltz ML, Reiter RJ, Herman TS (1999) Melatonin and protection from genetic damage in blood and bone marrow: Whole‐body irradiation studies in mice. J Pineal Res 27(4):221–225

    Article  PubMed  Google Scholar 

  • Michaeloudes C, Sukkar MB, Khorasani NM, Bhavsar PK, Chung KF (2011) TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells. Am J Phys Lung Cell Mol Phys 300(2):L295–L304

    CAS  Google Scholar 

  • Mihandoust E, Shirazi A (2010) Application of radioprotective agents in cancer treatment. Iran J Nucl Med 18(1):107–107

    Google Scholar 

  • Mohan N, Sadeghi K, Reiter RJ, Meltz ML (1995) The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-kappa B. Biochem Mol Biol Int 37(6):1063–1070

    CAS  PubMed  Google Scholar 

  • Muralidharan S, Mandrekar P (2013) Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol 94(6):1167–1184

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Najafi M, Fardid R, Hadadi Gh, Fardid M (2014) The Mechanisms of Radiation-Induced Bystander Effect. J Biomed Phys Eng 4(4):163-172.

  • Najafi M, Fardid R, Takhshid MA, Mosleh-Shirazi MA, Rezaeyan AH, Salajegheh A (2016) Radiation-induced oxidative stress at out-of-field lung tissues after pelvis irradiation in rats. Cell J 18(3):340–345

    PubMed  PubMed Central  Google Scholar 

  • Najafi M, Salajegheh A, Rezaeyan A (2017a) Bystander effect and second primary cancers following radiotherapy: What are its significances?. J Med Phys 42:55–56

  • Najafi M, Shirazi A, Motevaseli E, Rezaeyan AH, Salajegheh A, Rezapoor S (2017b) Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology. doi:10.1007/s10787-017-0332-5

  • Ortiz F, Acuña‐Castroviejo D, Doerrier C, Dayoub JC, López LC, Venegas C et al (2015) Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation‐induced oral mucositis. J Pineal Res 58(1):34–49

    Article  CAS  PubMed  Google Scholar 

  • Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW et al (2010) Melatonin suppresses tumor angiogenesis by inhibiting HIF‐1α stabilization under hypoxia. J Pineal Res 48(2):178–184

    Article  CAS  PubMed  Google Scholar 

  • Perrone G, Ruffini PA, Catalano V, Spino C, Santini D, Muretto P et al (2008) Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer (Oxford, England : 1990) 44(13):1875–1882

    Article  CAS  Google Scholar 

  • Persson HL, Kurz T, Eaton JW, Brunk UT (2005) Radiation-induced cell death: importance of lysosomal destabilization. Biochem J 389(3):877–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pockley AG (2012) Radiation-induced effects and the immune system in cancer. Radiat Induc Eff Immune Syst. 121

  • Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF (1994) Evidence for a direct action of melatonin on the immune system. Biol Signals 3(2):107–117

    Article  CAS  PubMed  Google Scholar 

  • Pozo D, Reiter RJ, Calvo JR, Guerrero JM (1994) Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci 55(24):PL455–PL460

    Article  CAS  PubMed  Google Scholar 

  • Pozo DA, Delgado M, Fernandez-Santos JM, Calvo JR, Gomariz RP, Martin-Lacave I et al (1997) Expression of the Mel1a-melatonin receptor mRNA in T and B subsets of lymphocytes from rat thymus and spleen. FASEB J 11(6):466–473

    CAS  PubMed  Google Scholar 

  • Prise KM, O’Sullivan JM (2009) Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 9(5):351–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raghavendra V, Singh V, Kulkarni SK, Agrewala JN (2001) Melatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Mol Cell Biochem 221(1–2):57–62

    Article  CAS  PubMed  Google Scholar 

  • Rayet B, Gelinas C (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18(49):6938–6947

    Article  CAS  PubMed  Google Scholar 

  • Reiter RJ, Meltz ML (1995) Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. Mutat Res Lett 346(1):23–31

    Article  Google Scholar 

  • Reiter RJ, Tan D-X, Qi W-B (1998) Suppression of oxygen toxicity by melatonin. Acta Pharmacol Sin 19(6):575–581

    CAS  Google Scholar 

  • Reiter RJ, Tan D-X, Burkhardt S (2002) Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech Ageing Dev 123(8):1007–1019

    Article  CAS  PubMed  Google Scholar 

  • Reiter RJ, Rosales-Corral SA, Manchester LC, Tan D-X (2013a) Peripheral reproductive organ health and melatonin: ready for prime time. Int J Mol Sci 14(4):7231–7272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reiter RJ, Tan D-X, Galano A (2013b) Melatonin reduces lipid peroxidation and membrane viscosity. Front Physiol 5:377

    Google Scholar 

  • Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre‐Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61(3):253–278

    Article  CAS  PubMed  Google Scholar 

  • Rezaeyan A, Fardid R, Haddadi GH, Takhshid MA, Hosseinzadeh M, Najafi M, Salajegheh A (2016a) Evaluating radioprotective effect of hesperidin on acute radiation damage in the lung tissue of rats. J Biomed Phys Eng 6(3):165–174

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rezaeyan A, Haddadi GH, Hosseinzadeh M, Moradi M, Najafi M (2016b) Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue. J Med Phys 41(3):182–191

    Article  PubMed  PubMed Central  Google Scholar 

  • Rock KL, Lai JJ, Kono H (2011) Innate and adaptive immune responses to cell death. Immunol Rev 243(1):191–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodel F, Frey B, Gaipl U, Keilholz L, Fournier C, Manda K et al (2012) Modulation of inflammatory immune reactions by low-dose ionizing radiation: molecular mechanisms and clinical application. Curr Med Chem 19(12):1741–1750

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V et al (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36(1):1–9

    Article  CAS  PubMed  Google Scholar 

  • Sainz RM, Reiter RJ, Tan DX, Roldan F, Natarajan M, Quiros I et al (2008) Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation‐induced apoptosis in prostate cancer cells in vitro. J Pineal Res 45(3):258–270

    Article  CAS  PubMed  Google Scholar 

  • Sánchez‐Hidalgo M, Lee M, de la Lastra CA, Guerrero JM, Packham G (2012) Melatonin inhibits cell proliferation and induces caspase activation and apoptosis in human malignant lymphoid cell lines. J Pineal Res 53(4):366–373

    Article  PubMed  CAS  Google Scholar 

  • Sangiuliano B, Pérez NM, Moreira DF, Belizário JE (2014) Cell death-associated molecular-pattern molecules: inflammatory signaling and control. Mediat Inflamm 2014:821043

    Article  CAS  Google Scholar 

  • Schmuth M, Wimmer MA, Hofer S, Sztankay A, Weinlich G, Linder D et al (2002) Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double‐blind study. Br J Dermatol 146(6):983–991

    Article  CAS  PubMed  Google Scholar 

  • Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ et al (2011) Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 1534735411425484

  • Şener G, Atasoy BM, Ersoy Y, Arbak S, Şengöz M, Yeğen BÇ (2004) Melatonin protects against ionizing radiation‐induced oxidative damage in corpus cavernosum and urinary bladder in rats. J Pineal Res 37(4):241–246

    Article  PubMed  CAS  Google Scholar 

  • Serin M, Gülbaş H, Gürses İ, Erkal HŞ, Yücel N (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):187–193

    Article  CAS  PubMed  Google Scholar 

  • Shi D, Xiao X, Wang J, Liu L, Chen W, Fu L et al (2012) Melatonin suppresses proinflammatory mediators in lipopolysaccharide‐stimulated CRL1999 cells via targeting MAPK, NF‐κB, c/EBPβ, and p300 signaling. J Pineal Res 53(2):154–165

    Article  CAS  PubMed  Google Scholar 

  • Shirazi A, Ghobadi G, Ghazi-Khansari M (2007) A radiobiological review on melatonin: a novel radioprotector. J Radiat Res 48(4):263–272

    Article  CAS  PubMed  Google Scholar 

  • Shirazi A, Mihandoost E, Mohseni M, Ghazi-Khansari M, Rabie Mahdavi S (2013) Radio-protective effects of melatonin against irradiation-induced oxidative damage in rat peripheral blood. Physica Medica 29(1):65–74

    Article  PubMed  Google Scholar 

  • Somosy Z (2000) Radiation response of cell organelles. Micron 31(2):165–181

    Article  CAS  PubMed  Google Scholar 

  • Szumiel I (2015) Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. Int J Radiat Biol 91(1):1–12

    Article  CAS  PubMed  Google Scholar 

  • Tahamtan R, Monfared AS, Tahamtani Y, Tavassoli A, Akmali M, Mosleh-Shirazi MA et al (2015) Radioprotective effect of melatonin on radiation-induced lung injury and lipid peroxidation in rats. Cell J 17(1):111–120

    PubMed  PubMed Central  Google Scholar 

  • Tain Y-L, Chen C-C, Lee C-T, Kao Y-H, Sheen J-M, Yu H-R et al (2013) Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C. Pediatr Res 73(4–1):395–401

    Article  CAS  PubMed  Google Scholar 

  • Tan D-X, Manchester LC, Reiter RJ, Qi W-B, Karbownik M, Calvo JR (2000) Significance of melatonin in antioxidative defense system: reactions and products. Neurosignals 9(3–4):137–159

    Article  CAS  Google Scholar 

  • Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (2007) One molecule, many derivatives: A never‐ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42(1):28–42

    Article  CAS  PubMed  Google Scholar 

  • Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C et al (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52(2):217–227

    Article  CAS  PubMed  Google Scholar 

  • Wu ZH, Miyamoto S (2007) Many faces of NF-kappaB signaling induced by genotoxic stress. J Mol Med (Berlin, Germany) 85(11):1187–1202

    Article  CAS  Google Scholar 

  • Wu CC, Lu KC, Lin GJ, Hsieh HY, Chu P, Lin SH et al (2012) Melatonin enhances endogenous heme oxygenase‐1 and represses immune responses to ameliorate experimental murine membranous nephropathy. J Pineal Res 52(4):460–469

    Article  CAS  PubMed  Google Scholar 

  • Wu KK, Cheng H-H, Chang T-C (2014) 5-methoxyindole metabolites of L-tryptophan: control of COX-2 expression, inflammation and tumorigenesis. J Biomed Sci 21(1):17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Q, Miller SC, Osmond DG (2000) Melatonin inhibits apoptosis during early B‐cell development in mouse bone marrow. J Pineal Res 29(2):86–93

    Article  PubMed  Google Scholar 

  • Zhang HM, Zhang Y, Zhang BX (2011) The role of mitochondrial complex III in melatonin‐induced ROS production in cultured mesangial cells. J Pineal Res 50(1):78–82

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Robbins ME (2009) Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem 16(2):130–143

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Yu T, Chen G, Brown SA, Yu Z, Mattson M et al (2001) Effects of NF-κB1 (p50) targeted gene disruption on ionizing radiation-induced NF-κB activation and TNFα, IL-1α, IL-1β and IL-6 mRNA expression in vivo. Int J Radiat Biol 77(7):763–772

    Article  CAS  PubMed  Google Scholar 

  • Zhou R, Wang R, Song J, Zhang H, Luo J, Liu H (2015) Melatonin inhibit the angiogenesis of gastric cancer by nuclear receptor. FASEB J 29(1 Supplement):639.5

    Google Scholar 

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Acknowledgments

Tehran University of Medical Sciences grant number 33480.

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Authors and Affiliations

  1. Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    M. Najafi, A. Shirazi & Gh. Geraily

  2. Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    E. Motevaseli

  3. Department of Medical Radiation Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran

    F. Norouzi

  4. Department of Radiology, Faculty of Paramedical, Tehran University of Medical Sciences, Tehran, Iran

    M. Heidari & S. Rezapoor

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  1. M. Najafi
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  2. A. Shirazi
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  3. E. Motevaseli
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  4. Gh. Geraily
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  5. F. Norouzi
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M. Najafi declares that he has no conflict of interest. A. Shirazi declares that he has no conflict of interest. E. Motevaseli declares that she has no conflict of interest. Gh. Geraily declares that she has no conflict of interest. F. Norouzi declares that he has no conflict of interest. M. Heidari declares that he has no conflict of interest. S Rezapoor declares that he has no conflict of interest.

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Najafi, M., Shirazi, A., Motevaseli, E. et al. The melatonin immunomodulatory actions in radiotherapy. Biophys Rev 9, 139–148 (2017). https://doi.org/10.1007/s12551-017-0256-8

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