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Volume 32, Issue 3
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Resistance to therapy and the toxicity of normal tissue are the major problems for efficacy associated with chemotherapy and radiotherapy. Drug resistance is responsible for most cases of mortality associated with cancer. Furthermore, their side effects can decrease the quality of life for surviving patients. An enhancement in the tumor response to therapy and alleviation of toxic effects remain unsolved challenges. One of the interesting topics is the administration of agents with low toxicity to protect normal tissues and/or sensitize cancers to chemo/radiotherapy. Melatonin is a natural body hormone that is known as a multitasking molecule. Although it has antioxidant properties, a large number of experiments have uncovered interesting effects of melatonin that can increase the therapeutic efficacy of chemo/radiation therapy. Melatonin can enhance anticancer therapy efficacy through various mechanisms, cells such as the immune system, and modulation of cell cycle and death pathways, tumor suppressor genes, and also through suppression of some drug resistance mediators. However, melatonin may protect normal tissues through the suppression of inflammation, fibrosis, and massive oxidative stress in normal cells and tissues. In this review, we will discuss the distinct effects of melatonin on both tumors and normal tissues. We review how melatonin may enhance radio/chemosensitivity of tumors while protecting normal tissues such as the lung, heart, gastrointestinal system, reproductive system, brain, liver, and kidney.

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2023-11-02
2025-01-17

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References

  1. BrayF. FerlayJ. SoerjomataramI. SiegelR.L. TorreL.A. JemalA. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.201868639442410.3322/caac.2149230207593
     [Google Scholar]
  2. NarodS. Can advanced-stage ovarian cancer be cured?Nat. Rev. Clin. Oncol.201613425526110.1038/nrclinonc.2015.22426787282
     [Google Scholar]
  3. HuangC.Y. JuD.T. ChangC.F. Muralidhar ReddyP. VelmuruganB.K. A review on the effects of current chemotherapy drugs and natural agents in treating non–small cell lung cancer.Biomedicine (Taipei)2017742310.1051/bmdcn/201707042329130448
     [Google Scholar]
  4. SrinivasU.S. TanB.W.Q. VellayappanB.A. JeyasekharanA.D. ROS and the DNA damage response in cancer.Redox Biol.20192510108410.1016/j.redox.2018.10108430612957
     [Google Scholar]
  5. YuD.L. LouZ.P. MaF.Y. NajafiM. The interactions of paclitaxel with tumour microenvironment.Int. Immunopharmacol.202210510855510.1016/j.intimp.2022.10855535121223
     [Google Scholar]
  6. SchaueD. McBrideW.H. T lymphocytes and normal tissue responses to radiation.Front. Oncol.2012211910.3389/fonc.2012.0011923050243
     [Google Scholar]
  7. WillersH. AzzoliC.G. SantivasiW.L. XiaF. Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer.Cancer J.201319320020710.1097/PPO.0b013e318292e4e323708066
     [Google Scholar]
  8. ZhangQ.Y. WangF.X. JiaK.K. KongL.D. Natural product interventions for chemotherapy and radiotherapy-induced side effects.Front. Pharmacol.20189125310.3389/fphar.2018.0125330459615
     [Google Scholar]
  9. LiL. LeungP.S. Use of herbal medicines and natural products: An alternative approach to overcoming the apoptotic resistance of pancreatic cancer.Int. J. Biochem. Cell Biol.20145322423610.1016/j.biocel.2014.05.02124875648
     [Google Scholar]
  10. Juhnevica-RadenkovaK. MorenoD.A. IkaseL. DrudzeI. RadenkovsV. Naturally occurring melatonin: Sources and possible ways of its biosynthesis.Compr. Rev. Food Sci. Food Saf.20201964008403010.1111/1541‑4337.1263933337029
     [Google Scholar]
  11. MuQ. NajafiM. Modulation of the tumor microenvironment (TME) by melatonin.Eur. J. Pharmacol.202190717436510.1016/j.ejphar.2021.17436534302814
     [Google Scholar]
  12. Acuña-CastroviejoD. EscamesG. VenegasC. Díaz-CasadoM.E. Lima-CabelloE. LópezL.C. Rosales-CorralS. TanD.X. ReiterR.J. Extrapineal melatonin: Sources, regulation, and potential functions.Cell. Mol. Life Sci.201471162997302510.1007/s00018‑014‑1579‑224554058
     [Google Scholar]
  13. SalehiB. SharopovF. FokouP. KobylinskaA. JongeL. TadioK. Sharifi-RadJ. PosmykM. MartorellM. MartinsN. IritiM. Melatonin in medicinal and food plants: Occurrence, bioavailability, and health potential for humans.Cells20198768110.3390/cells807068131284489
     [Google Scholar]
  14. YuH. DicksonE.J. JungS.R. KohD.S. HilleB. High membrane permeability for melatonin.J. Gen. Physiol.20161471637610.1085/jgp.20151152626712850
     [Google Scholar]
  15. Sánchez-BarcelóE.J. MediavillaM.D. TanD.X. ReiterR.J. Clinical uses of melatonin: Evaluation of human trials.Curr. Med. Chem.201017192070209510.2174/09298671079123368920423309
     [Google Scholar]
  16. CostelloR.B. LentinoC.V. BoydC.C. O’ConnellM.L. CrawfordC.C. SprengelM.L. DeusterP.A. The effectiveness of melatonin for promoting healthy sleep: A rapid evidence assessment of the literature.Nutr. J.201413110610.1186/1475‑2891‑13‑10625380732
     [Google Scholar]
  17. WangY.Y. ZhengW. NgC.H. UngvariG.S. WeiW. XiangY.T. Meta-analysis of randomized, double-blind, placebo-controlled trials of melatonin in Alzheimer’s disease.Int. J. Geriatr. Psychiatry2017321505710.1002/gps.457127645169
     [Google Scholar]
  18. HosseinzadehA. Javad-MoosaviS.A. ReiterR.J. YarahmadiR. GhaznaviH. MehrzadiS. Oxidative/nitrosative stress, autophagy and apoptosis as therapeutic targets of melatonin in idiopathic pulmonary fibrosis.Expert Opin. Ther. Targets201822121049106110.1080/14728222.2018.154131830445883
     [Google Scholar]
  19. ManchesterL.C. Coto-MontesA. BogaJ.A. AndersenL.P.H. ZhouZ. GalanoA. VriendJ. TanD.X. ReiterR.J. Melatonin: an ancient molecule that makes oxygen metabolically tolerable.J. Pineal Res.201559440341910.1111/jpi.1226726272235
     [Google Scholar]
  20. MoslehiM. MoazamiyanfarR. DakkaliM.S. RezaeiS. Rastegar-PouyaniN. JafarzadehE. MouludiK. KhodamoradiE. TaebS. NajafiM. Modulation of the immune system by melatonin; implications for cancer therapy.Int. Immunopharmacol.202210810889010.1016/j.intimp.2022.10889035623297
     [Google Scholar]
  21. SquatritoM. BrennanC.W. HelmyK. HuseJ.T. PetriniJ.H. HollandE.C. Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas.Cancer Cell201018661962910.1016/j.ccr.2010.10.03421156285
     [Google Scholar]
  22. XuJ.H. HuS.L. ShenG.D. ShenG. Tumor suppressor genes and their underlying interactions in paclitaxel resistance in cancer therapy.Cancer Cell Int.20161611310.1186/s12935‑016‑0290‑926900348
     [Google Scholar]
  23. WuX-y. XuW-W. HuanX. WuG. LiG. ZhouY-H. NajafiM. Mechanisms of cancer cell killing by metformin: A review on different cell death pathways.Mol. Cell. Biochem.202235771397
     [Google Scholar]
  24. PougetJ.P. GeorgakilasA.G. RavanatJ.L. Targeted and off-target (bystander and abscopal) effects of radiation therapy: Redox mechanisms and risk/benefit analysis.Antioxid. Redox Signal.201829151447148710.1089/ars.2017.726729350049
     [Google Scholar]
  25. YaranaC. St ClairD.K. Chemotherapy-induced tissue injury: An insight into the role of extracellular vesicles-mediated oxidative stress responses.Antioxidants2017647510.3390/antiox604007528956814
     [Google Scholar]
  26. MijatovićS. Savić-RadojevićA. Plješa-ErcegovacM. SimićT. NicolettiF. Maksimović-IvanićD. The double-faced role of nitric oxide and reactive oxygen species in solid tumors.Antioxidants20209537410.3390/antiox905037432365852
     [Google Scholar]
  27. ThomasD.C. The phagocyte respiratory burst: Historical perspectives and recent advances.Immunol. Lett.2017192889610.1016/j.imlet.2017.08.01628864335
     [Google Scholar]
  28. MoloneyJ.N. CotterT.G. ROS. Signallng in the biology of cancer. Semin. Cell. Dev. Biol. Elsevier; 2018Vol. 805064
     [Google Scholar]
  29. PerilloB. Di DonatoM. PezoneA. Di ZazzoE. GiovannelliP. GalassoG. CastoriaG. MigliaccioA. ROS in cancer therapy: The bright side of the moon.Exp. Mol. Med.202052219220310.1038/s12276‑020‑0384‑232060354
     [Google Scholar]
  30. PourhanifehM.H. MahdaviniaM. ReiterR.J. AsemiZ. Potential use of melatonin in skin cancer treatment: A review of current biological evidence.J. Cell. Physiol.20192348121421214810.1002/jcp.2812930618091
     [Google Scholar]
  31. ZhengJ. Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review).Oncol. Lett.2012461151115710.3892/ol.2012.92823226794
     [Google Scholar]
  32. YadavN. ChandraD. Mitochondrial DNA mutations and breast tumorigenesis.Biochim. Biophys. Acta20131836233634424140413
     [Google Scholar]
  33. ZhangB. WangD. GuoF. XuanC. Mitochondrial membrane potential and reactive oxygen species in cancer stem cells.Fam. Cancer2015141192310.1007/s10689‑014‑9757‑925266577
     [Google Scholar]
  34. ShinY.Y. SeoY. OhS.J. AhnJ.S. SongM. KangM.J. OhJ.M. LeeD. KimY.H. SungE.S. KimH.S. Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics.J. Pineal Res.2022721e1277910.1111/jpi.1277934826168
     [Google Scholar]
  35. ShimuraT. NomaN. SanoY. OchiaiY. OikawaT. FukumotoM. KunugitaN. AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells.Radiother. Oncol.2014112230230710.1016/j.radonc.2014.07.01525150637
     [Google Scholar]
  36. LiuK.X. EverdellE. PalS. Haas-KoganD.A. MilliganM.G. Harnessing lactate metabolism for radiosensitization.Front. Oncol.20211167233910.3389/fonc.2021.67233934367959
     [Google Scholar]
  37. FarhoodB. GoradelN.H. MortezaeeK. KhanlarkhaniN. SalehiE. NashtaeiM.S. Mirtavoos-mahyariH. MotevaseliE. ShabeebD. MusaA.E. NajafiM. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization.Clin. Transl. Oncol.201921326827910.1007/s12094‑018‑1934‑030136132
     [Google Scholar]
  38. Guerra-LibreroA. Fernandez-GilB.I. FloridoJ. Martinez-RuizL. Rodríguez-SantanaC. ShenY.Q. García-VerdugoJ.M. López-RodríguezA. RusanovaI. Quiñones-HinojosaA. Acuña-CastroviejoD. MarruecosJ. De HaroT. EscamesG. Melatonin targets metabolism in head and neck cancer cells by regulating mitochondrial structure and function.Antioxidants202110460310.3390/antiox1004060333919790
     [Google Scholar]
  39. EscamesG. Fernández-GilB.I. Guerra-LibreroA. ShenY. García-LópezS. FloridoJ. SayedR. Acuña-CastroviejoD. EspositoJ. PO-089: Melatonin enhances the toxicity of radio- and chemotherapy in head and neck cancer cells.Radiother. Oncol.20171224310.1016/S0167‑8140(17)30223‑2
     [Google Scholar]
  40. Fernandez-GilB.I. Guerra-LibreroA. ShenY.Q. FloridoJ. Martínez-RuizL. García-LópezS. AdanC. Rodríguez-SantanaC. Acuña-CastroviejoD. Quiñones-HinojosaA. Fernández-MartínezJ. Abdel MoneimA.E. LópezL.C. Rodríguez FerrerJ.M. EscamesG. Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ros generation, apoptosis, and autophagy.Oxid. Med. Cell. Longev.2019201911210.1155/2019/718712830944696
     [Google Scholar]
  41. SainzR.M. ReiterR.J. TanD.X. RoldanF. NatarajanM. QuirosI. HeviaD. RodriguezC. MayoJ.C. 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.200845325827010.1111/j.1600‑079X.2008.00585.x18384530
     [Google Scholar]
  42. OkumuraN. YoshidaH. KitagishiY. NishimuraY. MatsudaS. Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer.Biochem. Biophys. Res. Commun.2011413339539910.1016/j.bbrc.2011.08.09821893034
     [Google Scholar]
  43. SongM.S. SalmenaL. PandolfiP.P. The functions and regulation of the PTEN tumour suppressor.Nat. Rev. Mol. Cell Biol.201213528329610.1038/nrm333022473468
     [Google Scholar]
  44. LeeJ-J. KimB.C. ParkM-J. LeeY-S. KimY-N. LeeB.L. LeeJ-S. PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation.Cell Death Differ.201118466667710.1038/cdd.2010.13921072054
     [Google Scholar]
  45. OngA.L.C. RamasamyT.S. Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming.Ageing Res. Rev.201843648010.1016/j.arr.2018.02.00429476819
     [Google Scholar]
  46. HuangJ. ChangZ. LuQ. ChenX. NajafiM. Nobiletin as an inducer of programmed cell death in cancer: A review.Apoptosis2022275-629731010.1007/s10495‑022‑01721‑435312885
     [Google Scholar]
  47. YuC. YangB. NajafiM. Targeting of cancer cell death mechanisms by curcumin: Implications to cancer therapy.Basic Clin. Pharmacol. Toxicol.2021129639741510.1111/bcpt.1364834473898
     [Google Scholar]
  48. FuX. LiM. TangC. HuangZ. NajafiM. Targeting of cancer cell death mechanisms by resveratrol: A review.Apoptosis20212611-1256157310.1007/s10495‑021‑01689‑734561763
     [Google Scholar]
  49. WangZ. LiuY. MusaA.E. Regulation of cell death mechanisms by melatonin: Implications in cancer therapy.Anticancer Agents Med. Chem.2022221120802090
     [Google Scholar]
  50. BrandmaierA. HouS.Q. DemariaS. FormentiS.C. ShenW.H. PTEN at the interface of immune tolerance and tumor suppression.Front. Biol.201712316317410.1007/s11515‑017‑1443‑529527223
     [Google Scholar]
  51. MaH. WangZ. HuL. ZhangS. ZhaoC. YangH. WangH. FangZ. WuL. ChenX. The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas.Biochem. Biophys. Res. Commun.201849641322133010.1016/j.bbrc.2018.02.01029408377
     [Google Scholar]
  52. SongJ. MaS.J. LuoJ.H. ZhangH. WangR.X. LiuH. LiL. ZhangZ.G. ZhouR.X. Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway.Oncol. Rep.20183941975198310.3892/or.2018.628229484412
     [Google Scholar]
  53. ProiettiS. CucinaA. D’AnselmiF. DinicolaS. PasqualatoA. LisiE. BizzarriM. Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells.J. Pineal Res.201150215015821091766
     [Google Scholar]
  54. Alonso-GonzálezC. González-AbaldeC. Menéndez-MenéndezJ. González-GonzálezA. Álvarez-GarcíaV. González-CabezaA. Martínez-CampaC. CosS. Melatonin modulation of radiation-induced molecular changes in mcf-7 human breast cancer cells.Biomedicines2022105108810.3390/biomedicines1005108835625825
     [Google Scholar]
  55. MoradianF. PourhanifehM.H. MehrzadiS. Karimi-BehnaghA. HosseinzadehA. Therapeutic potentials of melatonin in the treatment of lymphoma: A review of current evidence.202210.1111/fcp.12780
     [Google Scholar]
  56. HuM. ZhuS. XiongS. XueX. ZhouX. MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review).Oncol. Rep.20194131439145410.3892/or.2019.696230628706
     [Google Scholar]
  57. RahmaniF. ZiaeemehrA. ShahidsalesS. GharibM. KhazaeiM. FernsG.A. RyzhikovM. AvanA. HassanianS.M. Role of regulatory miRNAs of the PI3K/AKT/mTOR signaling in the pathogenesis of hepatocellular carcinoma.J. Cell. Physiol.202023554146415210.1002/jcp.2933331663122
     [Google Scholar]
  58. ZhengC. TangF. MinL. HornicekF. DuanZ. TuC. PTEN in osteosarcoma: Recent advances and the therapeutic potential.Biochim. Biophys. Acta Rev. Cancer20201874218840510.1016/j.bbcan.2020.18840532827577
     [Google Scholar]
  59. JiaH. SunW. LiX. XuW. Melatonin promotes apoptosis of thyroid cancer cells via regulating the signaling of microRNA-21 (miR-21) and microRNA-30e (miR-30e).Bioengineered20221349588960110.1080/21655979.2022.205420635412442
     [Google Scholar]
  60. SantoroR. MaraniM. BlandinoG. MutiP. StranoS. Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation.Oncogene201231242931294210.1038/onc.2011.46922002314
     [Google Scholar]
  61. HosseiniF. ShanehbandiD. SoleimanpourJ. YousefiB. AlemiF. Melatonin increases the sensitivity of osteosarcoma cells to chemotherapy drug cisplatin.Drug Res.202272631231810.1055/a‑1830‑871635636434
     [Google Scholar]
  62. AhsanH. WhittemoreA.S. ChenY. SenieR.T. HamiltonS.P. WangQ. GurvichI. SantellaR.M. Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study.Breast Cancer Res.200471R71R8110.1186/bcr95115642171
     [Google Scholar]
  63. HuaH. ZhangH. KongQ. JiangY. Mechanisms for estrogen receptor expression in human cancer.Exp. Hematol. Oncol.2018712410.1186/s40164‑018‑0116‑730250760
     [Google Scholar]
  64. BallL.J. PaleshO. KriegsfeldL.J. The pathophysiologic role of disrupted circadian and neuroendocrine rhythms in breast carcinogenesis.Endocr. Rev.201637545046610.1210/er.2015‑113327712099
     [Google Scholar]
  65. LopesJ. ArnostiD. TroskoJ.E. TaiM.H. ZuccariD. Melatonin decreases estrogen receptor binding to estrogen response elements sites on the OCT4 gene in human breast cancer stem cells.Genes Cancer201675-620921710.18632/genesandcancer.10727551335
     [Google Scholar]
  66. del RíoB. PedreroJ.M.G. Martínez-CampaC. ZuazuaP. LazoP.S. RamosS. Melatonin, an endogenous-specific inhibitor of estrogen receptor α via calmodulin.J. Biol. Chem.200427937382943830210.1074/jbc.M40314020015229223
     [Google Scholar]
  67. KieferT. RamP.T. YuanL. HillS.M. Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells.Breast Cancer Res. Treat.2002711374510.1023/A:101330140846411859872
     [Google Scholar]
  68. KanishiY. KobayashiY. NodaS. IshizukaB. SaitoK. Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines.J. Pineal Res.200028422723310.1034/j.1600‑079X.2000.280405.x10831158
     [Google Scholar]
  69. PetrankaJ. BaldwinW. BiermannJ. JayadevS. BarrettJ.C. MurphyE. The oncostatic action of melatonin in an ovarian carcinoma cell line.J. Pineal Res.199926312913610.1111/j.1600‑079X.1999.tb00574.x10231725
     [Google Scholar]
  70. HagströmA. Kal OmarR. WilliamsP.A. StålhammarG. The rationale for treating uveal melanoma with adjuvant melatonin: A review of the literature.BMC Cancer202222139810.1186/s12885‑022‑09464‑w35413810
     [Google Scholar]
  71. Alonso-GonzálezC. GonzálezA. Martínez-CampaC. Menéndez-MenéndezJ. Gómez-ArozamenaJ. García-VidalA. CosS. Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis.Cancer Lett.2016370114515210.1016/j.canlet.2015.10.01526497762
     [Google Scholar]
  72. Márquez-GarbánD.C. ChenH.W. GoodglickL. FishbeinM.C. PietrasR.J. Targeting aromatase and estrogen signaling in human non-small cell lung cancer.Ann. N. Y. Acad. Sci.20091155119420510.1111/j.1749‑6632.2009.04116.x19250205
     [Google Scholar]
  73. WangY. LiS. ZhuL. ZouJ. JiangX. ChenM. ChenB. Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1.Clin. Transl. Oncol.20192181026103310.1007/s12094‑018‑02019‑130712236
     [Google Scholar]
  74. TaubeJ.M. GalonJ. ShollL.M. RodigS.J. CottrellT.R. GiraldoN.A. BarasA.S. PatelS.S. AndersR.A. RimmD.L. Cimino-MathewsA. Implications of the tumor immune microenvironment for staging and therapeutics.Mod. Pathol.201831221423410.1038/modpathol.2017.15629192647
     [Google Scholar]
  75. GajewskiT.F. MengY. BlankC. BrownI. KachaA. KlineJ. HarlinH. Immune resistance orchestrated by the tumor microenvironment.Immunol. Rev.2006213113114510.1111/j.1600‑065X.2006.00442.x16972901
     [Google Scholar]
  76. MhaidlyR. Mechta-GrigoriouF. In Semin Immunol.Elsevier2020Vol. 48101417
     [Google Scholar]
  77. WeissT. WellerM. RothP. Immunological effects of chemotherapy and radiotherapy against brain tumors.Expert Rev. Anticancer Ther.201616101087109410.1080/14737140.2016.122960027598516
     [Google Scholar]
  78. MirS.M. AliarabA. GoodarziG. ShirzadM. JafariS.M. QujeqD. Samavarchi TehraniS. AsadiJ. Melatonin: A smart molecule in the DNA repair system.Cell Biochem. Funct.202240141610.1002/cbf.367234672014
     [Google Scholar]
  79. ShiraziA. RezapoorS. AbbasiS. BazzazJ. IzadiP. RezaeejamH. ValizadehM. Soleimani-MohammadiF. NajafiM. Modulation of radiation-induced base excision repair pathway gene expression by melatonin.J. Med. Phys.201742424525010.4103/jmp.JMP_9_1729296039
     [Google Scholar]
  80. AshrafizadehM. FarhoodB. Eleojo MusaA. TaebS. NajafiM. The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives.Int. Immunopharmacol.20208710680710.1016/j.intimp.2020.10680732683299
     [Google Scholar]
  81. AshrafizadehM. FarhoodB. Eleojo MusaA. TaebS. RezaeyanA. NajafiM. Abscopal effect in radioimmunotherapy.Int. Immunopharmacol.20208510666310.1016/j.intimp.2020.10666332521494
     [Google Scholar]
  82. LuoX. ChenY. TangH. WangH. JiangE. ShaoZ. LiuK. ZhouX. ShangZ. Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC.Cancer Sci.202211372232224510.1111/cas.1533835298069
     [Google Scholar]
  83. GaiotteL.B. CesárioR.C. SilveiraH.S. De Morais OliveiraD.A. CucieloM.S. RomagnoliG.G. KanenoR. De Campos ZuccariD.A.P. ReiterR.J. ChuffaL.G.A. Combination of melatonin with paclitaxel reduces the TLR4-mediated inflammatory pathway, PD-L1 levels, and survival of ovarian carcinoma cells.Melatonin Research202251345110.32794/mr112500118
     [Google Scholar]
  84. MortezaeeK. MajidpoorJ. Key promoters of tumor hallmarks.Int. J. Clin. Oncol.202111434773527
     [Google Scholar]
  85. FukumuraD. JainR.K. Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalization.Microvasc. Res.2007742-3728410.1016/j.mvr.2007.05.00317560615
     [Google Scholar]
  86. DanceaH. ShareefM.M. AhmedM.M. Role of radiation-induced TGF-beta signaling in cancer therapy.Mol. Cell. Pharmacol.200911445610.4255/mcpharmacol.09.0620336170
     [Google Scholar]
  87. NiuY.N. XiaS.J. Stroma–epithelium crosstalk in prostate cancer.Asian J. Androl.2009111283510.1038/aja.2008.3919098934
     [Google Scholar]
  88. FanF. SchimmingA. JaegerD. PodarK. Targeting the tumor microenvironment: Focus on angiogenesis.J Oncol2012201228126110.1155/2012/281261
     [Google Scholar]
  89. EstarasM. MartinezR. GarcíaA. Ortiz-PlacinC. IovannaJ.L. Santofimia-CastañoP. GonzalezA. Melatonin modulates metabolic adaptation of pancreatic stellate cells subjected to hypoxia.Biochem. Pharmacol.202220211511810.1016/j.bcp.2022.11511835671789
     [Google Scholar]
  90. ColomboJ. MacielJ.M.W. FerreiraL.C. Da SilvaR.F. ZuccariD.A.P. Effects of melatonin on HIF-1α and VEGF expression and on the invasive properties of hepatocarcinoma cells.Oncol. Lett.201612123123710.3892/ol.2016.460527347130
     [Google Scholar]
  91. ChengJ. YangH.L. GuC.J. LiuY.K. ShaoJ. ZhuR. HeY.Y. ZhuX.Y. LiM.Q. Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF.Int. J. Mol. Med.201943294595530569127
     [Google Scholar]
  92. KubatkaP. BojkováB. KassayováM. OrendášP. KajoK. VýbohováD. KružliakP. AdamicováK. PéčM. StollárováN. AdamkovM. Combination of Pitavastatin and melatonin shows partial antineoplastic effects in a rat breast carcinoma model.Acta Histochem.201411681454146110.1016/j.acthis.2014.09.01025450902
     [Google Scholar]
  93. OrendášP. KubatkaP. BojkováB. KassayováM. KajoK. VýbohováD. KružliakP. PéčM. AdamkovM. KapinováA. AdamicováK. SadloňováV. ChmelováM. StollárováN. Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model.Int. J. Exp. Pathol.201495640141010.1111/iep.1209425270735
     [Google Scholar]
  94. XuZ. ZhangY. DaiH. HanB. Epithelial–mesenchymal transition-mediated tumor therapeutic resistance.Molecules20222715475010.3390/molecules2715475035897925
     [Google Scholar]
  95. NantajitD. LinD. LiJ.J. The network of epithelial–mesenchymal transition: potential new targets for tumor resistance.J. Cancer Res. Clin. Oncol.2015141101697171310.1007/s00432‑014‑1840‑y25270087
     [Google Scholar]
  96. González-GonzálezA. GonzálezA. RuedaN. Alonso-GonzálezC. MenéndezJ.M. Martínez-CampaC. MitolaS. CosS. Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process.Sci. Rep.2020101479010.1038/s41598‑020‑61622‑x32179814
     [Google Scholar]
  97. WangX. WangB. ZhanW. KangL. ZhangS. ChenC. HouD. YouR. HuangH. Melatonin inhibits lung metastasis of gastric cancer in vivo. Biomed. Pharmacother.201911710901810.1016/j.biopha.2019.10901831176166
     [Google Scholar]
  98. González-GonzálezA. GonzálezA. RuedaN. Alonso-GonzálezC. Menéndez-MenéndezJ. Gómez-ArozamenaJ. Martínez-CampaC. CosS. Melatonin enhances the usefulness of ionizing radiation: Involving the regulation of different steps of the angiogenic process.Front. Physiol.20191087910.3389/fphys.2019.0087931354524
     [Google Scholar]
  99. BhandariM. RajS. ManchandaR. AlamM.S. Review on natural bioactive products as radioprotective therapeutics: Present and past perspective.Curr. Pharm. Biotechnol.202223141721173810.2174/138920102366622011010464535016594
     [Google Scholar]
  100. KingM. JosephS. AlbertA. ThomasT.V. NittalaM.R. WoodsW.C. VijayakumarS. PackianathanS. Use of amifostine for cytoprotection during radiation therapy: A review.Oncology2020982618010.1159/00050297931846959
     [Google Scholar]
  101. JaćevićV. Dragojević-SimićV. TatomirovićŽ. DobrićS. BokonjićD. KovačevićA. NepovimovaE. VališM. KučaK. The efficacy of amifostine against multiple-dose doxorubicin-induced toxicity in rats.Int. J. Mol. Sci.2018198237010.3390/ijms1908237030103540
     [Google Scholar]
  102. Al-JammazI. Al-OtaibiB. Aboul-EneinH. AmarteyJ.K. Synthesis and biodistribution of 2-[123I]iodomelatonin in normal mice.Appl. Radiat. Isot.2006641384210.1016/j.apradiso.2005.06.01216131471
     [Google Scholar]
  103. SheikholeslamiS. AryafarT. Abedi-FirouzjahR. BanaeiA. Dorri-GivM. ZamaniH. AtaeiG. MajdaeenM. FarhoodB. The role of melatonin on radiation-induced pneumonitis and lung fibrosis: A systematic review.Life Sci.202128111972110.1016/j.lfs.2021.11972134146555
     [Google Scholar]
  104. DhamijaE. MeenaP. RamalingamV. SahooR. RastogiS. ThulkarS. Chemotherapy-induced pulmonary complications in cancer: Significance of clinicoradiological correlation.Indian J. Radiol. Imaging2020301202610.4103/ijri.IJRI_178_1932476746
     [Google Scholar]
  105. DominicA. HamiltonD. AbeJ. Mitochondria and chronic effects of cancer therapeutics: The clinical implications.J. Thromb. Thrombolysis202151488488910.1007/s11239‑020‑02313‑233079380
     [Google Scholar]
  106. WeiJ. WangB. WangH. MengL. ZhaoQ. LiX. XinY. JiangX. Radiation-induced normal tissue damage: Oxidative stress and epigenetic mechanisms.Oxid. Med. Cell Longev.20192019301034210.1155/2019/3010342
     [Google Scholar]
  107. Croasdell LucchiniA. GachanjaN.N. RossiA.G. DorwardD.A. LucasC.D. Epithelial cells and inflammation in pulmonary wound repair.Cells202110233910.3390/cells1002033933562816
     [Google Scholar]
  108. JangS.S. KimH.G. LeeJ.S. HanJ.M. ParkH.J. HuhG.J. SonC.G. Melatonin reduces X-ray radiation-induced lung injury in mice by modulating oxidative stress and cytokine expression.Int. J. Radiat. Biol.20138929710510.3109/09553002.2013.73494323046278
     [Google Scholar]
  109. YildirimZ. KotukM. ErdoganH. IrazM. YagmurcaM. KukuI. FadilliogluE. Preventive effect of melatonin on bleomycin-induced lung fibrosis in rats.J. Pineal Res.2006401273310.1111/j.1600‑079X.2005.00272.x16313495
     [Google Scholar]
  110. GenoveseT. PaolaR.D. MazzonE. MuiàC. CaputiA.P. CuzzocreaS. Melatonin limits lung injury in bleomycin treated mice.J. Pineal Res.200539210511210.1111/j.1600‑079X.2005.00229.x16098086
     [Google Scholar]
  111. FarhoodB. AliasgharzadehA. AminiP. RezaeyanA. TavassoliA. MotevaseliE. ShabeebD. Eleojo MusaA. NajafiM. Mitigation of radiation-induced lung pneumonitis and fibrosis using metformin and melatonin: A histopathological study.Medicina201955841710.3390/medicina5508041731366142
     [Google Scholar]
  112. NguyenH.Q. ToN.H. ZadigueP. KerbratS. De La TailleA. Le GouvelloS. BelkacemiY. Ionizing radiation-induced cellular senescence promotes tissue fibrosis after radiotherapy. A review.Crit. Rev. Oncol. Hematol.2018129132610.1016/j.critrevonc.2018.06.01230097231
     [Google Scholar]
  113. LaiX. NajafiM. Redox interactions in chemo/radiation therapy-induced lung toxicity; mechanisms and therapy perspectives.Curr. Drug Targets202223131261127610.2174/138945012366622070512331535792117
     [Google Scholar]
  114. NajafiM. ShiraziA. MotevaseliE. GerailyG. AminiP. TooliL.F. ShabeebD. Melatonin modulates regulation of NOX2 and NOX4 following irradiation in the lung.Curr. Clin. Pharmacol.201914322423110.2174/157488471466619050215173331057124
     [Google Scholar]
  115. NajafiM. ShiraziA. MotevaseliE. GerailyG. AminiP. ShabeebD. Eleojo MusaA. Evaluating the expression of NOX2 and NOX4 signaling pathways in rats’ lung tissues following local chest irradiation; Modulatory effect of melatonin.Int. J. Mol. Cell. Med.20187422022531516881
     [Google Scholar]
  116. AliasgharzadehA. FarhoodB. AminiP. SaffarH. MotevaseliE. RezapoorS. NouruziF. ShabeebD.H. Eleojo MusaA. MohseniM. MoradiH. NajafiM. Melatonin attenuates upregulation of duox1 and duox2 and protects against lung injury following chest irradiation in rats.Cell J.201921323624231210428
     [Google Scholar]
  117. LiuB. RongY. SunD. LiW. ChenH. CaoB. WangT. Costunolide inhibits pulmonary fibrosis via regulating NF-kB and TGF-β1/Smad2/Nrf2-NOX4 signaling pathways.Biochem. Biophys. Res. Commun.2019510232933310.1016/j.bbrc.2019.01.10430709583
     [Google Scholar]
  118. CarnesecchiS. DeffertC. DonatiY. BassetO. HinzB. Preynat-SeauveO. GuichardC. ArbiserJ.L. BanfiB. PacheJ.C. Barazzone-ArgiroffoC. KrauseK.H. A key role for NOX4 in epithelial cell death during development of lung fibrosis.Antioxid. Redox Signal.201115360761910.1089/ars.2010.382921391892
     [Google Scholar]
  119. FangL. WangW. ChenJ. ZuoA. GaoH. YanT. WangP. LuY. LvR. XuF. Osthole attenuates bleomycin-induced pulmonary fibrosis by modulating NADPH oxidase 4-derived oxidative stress in mice.Oxid. Med. Cell Longev.202120213309944
     [Google Scholar]
  120. ZhaoH. WuQ.Q. CaoL.F. QingH.Y. ZhangC. ChenY.H. WangH. LiuR.R. XuD.X. Melatonin inhibits endoplasmic reticulum stress and epithelial-mesenchymal transition during bleomycin-induced pulmonary fibrosis in mice.PLoS One201495e9726610.1371/journal.pone.009726624818755
     [Google Scholar]
  121. FardidR. SalajeghehA. Mosleh-ShiraziM.A. SharifzadehS. OkhovatM.A. NajafiM. RezaeyanA. AbaszadehA. Melatonin ameliorates the production of COX-2, iNOS, and the formation of 8-OHdG in non-targeted lung tissue after pelvic irradiation.Cell J.201719232433128670525
     [Google Scholar]
  122. KarimfarM.H. RostamiS. HaghaniK. BakhtiyariS. Noori-ZadehA. Melatonin alleviates bleomycin-induced pulmonary fibrosis in mice.J. Biol. Regul. Homeost. Agents201529232733426122220
     [Google Scholar]
  123. WangZ. ZhangS. XiaoY. ZhangW. WuS. QinT. YueY. QianW. LiL. NLRP3 inflammasome and inflammatory diseases.Oxid. Med. Cell Longev.20202020406356210.1155/2020/4063562
     [Google Scholar]
  124. WuX. JiH. WangY. GuC. GuW. HuL. ZhuL. Melatonin alleviates radiation-induced lung injury via regulation of miR-30e/NLRP3 axis.Oxid. Med. Cell. Longev.2019201911410.1155/2019/408729830755784
     [Google Scholar]
  125. HuangJ.J. XiaJ. HuangL.L. LiY.C. HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury.Mol. Med. Rep.20192043424343210.3892/mmr.2019.1057531432144
     [Google Scholar]
  126. LiangQ. CaiW. ZhaoY. XuH. TangH. ChenD. QianF. SunL. Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis.Pharmacol. Res.202015810488410.1016/j.phrs.2020.10488432428667
     [Google Scholar]
  127. PanpanT. YuchenD. XianyongS. MengL. RuijuanH. RanranD. PengyanZ. MingxiL. RongrongX. Cardiac remodelling following cancer therapy: A review.Cardiovasc. Toxicol.202222977178610.1007/s12012‑022‑09762‑635877038
     [Google Scholar]
  128. FuX. TangJ. WenP. HuangZ. NajafiM. Redox interactions-induced cardiac toxicity in cancer therapy.Arch. Biochem. Biophys.202170810895210.1016/j.abb.2021.10895234097901
     [Google Scholar]
  129. ChoiK.J. NamJ.K. KimJ.H. ChoiS.H. LeeY.J. Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage.Exp. Mol. Med.202052578179210.1038/s12276‑020‑0439‑432467609
     [Google Scholar]
  130. Dragojevic-SimicV.M. DobricS.L.J. BokonjicD.R. VucinicZ.M. SinovecS.M. JacevicV.M. DogovicN.P. Amifostine protection against doxorubicin cardiotoxicity in rats.Anticancer Drugs200415216917810.1097/00001813‑200402000‑0001115075674
     [Google Scholar]
  131. Gursesİ. OzerenM. SerinM. YucelN. ErkalH. Histopathological efficiency of amifostine in radiation-induced heart disease in rats.Bratisl Lek Listy.201811915459
     [Google Scholar]
  132. GuJ. ZhuS. LiX. WuH. LiY. HuaF. Effect of amifostine in head and neck cancer patients treated with radiotherapy: A systematic review and meta-analysis based on randomized controlled trials.PLoS One201495e9596810.1371/journal.pone.009596824788761
     [Google Scholar]
  133. ÖzE. ErbaşD. SürücüH.S. DüzgünE. Prevention of doxorubicin-induced cardiotoxicity by melatonin.Mol. Cell. Biochem.20062821-2313710.1007/s11010‑006‑1153‑916317509
     [Google Scholar]
  134. ZhangY. LiL. XiangC. MaZ. MaT. ZhuS. Protective effect of melatonin against Adriamycin-induced cardiotoxicity.Exp. Ther. Med.2013551496150010.3892/etm.2013.98923737906
     [Google Scholar]
  135. SunX. SunP. ZhenD. XuX. YangL. FuD. WeiC. NiuX. TianJ. LiH. Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression.Toxicol. Appl. Pharmacol.202243711590210.1016/j.taap.2022.11590235093381
     [Google Scholar]
  136. ReD.P.D. Hippo signaling in the heart – non-canonical pathways impact growth, survival and function.Circ. J.20168071504151010.1253/circj.CJ‑16‑042627296131
     [Google Scholar]
  137. LiH. WangC. SunP. LiuD. DuG. TianJ. Melatonin attenuates doxorubicin-induced cardiotoxicity through preservation of YAP expression.J. Cell. Mol. Med.20202463634364610.1111/jcmm.1505732068341
     [Google Scholar]
  138. LiuX. ChenZ. ChuaC.C. MaY.S. YoungbergG.A. HamdyR. ChuaB.H.L. Melatonin as an effective protector against doxorubicin-induced cardiotoxicity.Am. J. Physiol. Heart Circ. Physiol.20022831H254H26310.1152/ajpheart.01023.200112063298
     [Google Scholar]
  139. ArinnoA. ManeechoteC. KhuanjingT. OngnokB. PrathumsapN. ChunchaiT. ArunsakB. KerdphooS. ShinlapawittayatornK. ChattipakornS.C. ChattipakornN. Cardioprotective effects of melatonin and metformin against doxorubicin-induced cardiotoxicity in rats are through preserving mitochondrial function and dynamics.Biochem. Pharmacol.202119211474310.1016/j.bcp.2021.11474334453902
     [Google Scholar]
  140. LiuD. AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis.Free Radic. Biol. Med.20181295972
     [Google Scholar]
  141. GhanimW. GhalibM. Al-YousofK. Study the prophylactic effects of melatonin and cyanocobalamin against cyclophosphamide-induced cardiotoxicity. Bull. Pharm. Sci.Assiut2022
     [Google Scholar]
  142. ZhuoX. JiangH. Protective effects of melatonin in cisplatin-induced cardiac toxicity: Possible role of BDNF-TNF-α signaling pathway.Acta Cir. Bras.2022372e37020810.1590/acb37020835507972
     [Google Scholar]
  143. Gürsesİ. ÖzerenM. SerinM. YücelN. ErkalH.Ş. Histopathological evaluation of melatonin as a protective agent in heart injury induced by radiation in a rat model.Pathol. Res. Pract.20142101286387110.1016/j.prp.2014.08.00625249491
     [Google Scholar]
  144. AbadiS.H.M.H. ShiraziA. AlizadehA.M. ChangiziV. NajafiM. KhalighfardS. NosratiH. The effect of melatonin on superoxide dismutase and glutathione peroxidase activity, and malondialdehyde levels in the targeted and the non-targeted lung and heart tissues after irradiation in xenograft mice colon cancer.Curr. Mol. Pharmacol.201811432633510.2174/187446721166618083015015430173656
     [Google Scholar]
  145. AryafarT. AminiP. RezapoorS. ShabeebD. Eleojo MusaA. NajafiM. ShiraziA. Modulation of radiation-induced nadph oxidases in rat’s heart tissues by melatonin.J. Biomed. Phys. Eng.202111446547234458194
     [Google Scholar]
  146. FarhoodB. AliasgharzadehA. AminiP. SaffarH. MotevaseliE. RezapoorS. NouruziF. ShabeebD. Eleojo MusaA. AshabiG. MohseniM. MoradiH. NajafiM. Radiation-induced dual oxidase upregulation in rat heart tissues: Protective effect of melatonin.Medicina.201955731710.3390/medicina5507031731252673
     [Google Scholar]
  147. RazmaraF. KhayamzadehM. An investigation into the prevalence and treatment of oral mucositis after cancer treatment.Int. J. Cancer Manag.2019121110.5812/ijcm.88405
     [Google Scholar]
  148. PulitoC. CristaudoA. PortaC.L. ZapperiS. BlandinoG. MorroneA. StranoS. Oral mucositis: the hidden side of cancer therapy.J. Exp. Clin. Cancer Res.202039121010.1186/s13046‑020‑01715‑733028357
     [Google Scholar]
  149. SubramaniamN. MuthukrishnanA. Oral mucositis and microbial colonization in oral cancer patients undergoing radiotherapy and chemotherapy: A prospective analysis in a tertiary care dental hospital.J. Investig. Clin. Dent.2019104e1245410.1111/jicd.1245431454171
     [Google Scholar]
  150. LiB. ShaoS. YuanL. JiaR. SunJ. JiQ. SuiH. ZhouL. ZhangY. LiuH. LiQ. WangY. ZhangB. Effects of mild moxibustion on intestinal microbiome and NLRP3 inflammasome in rats with 5-fluorouracil-induced intestinal mucositis.J. Integr. Med.202119214415710.1016/j.joim.2020.12.00433353843
     [Google Scholar]
  151. LangW. ChengM. ZhengX. ZhaoY. QuY. JiaZ. GongH. AliI. TangJ. ZhangH. Forsythiaside A alleviates methotrexate-induced intestinal mucositis in rats by modulating the NLRP3 signaling pathways.Int. Immunopharmacol.202210310846610.1016/j.intimp.2021.10846634933162
     [Google Scholar]
  152. NaiduM.U.R. RamanaG.V. RaniP.U. MohanK. SumanA. RoyP. Chemotherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treatment of cancer.Neoplasia20046542343110.1593/neo.0416915548350
     [Google Scholar]
  153. OrtizF. Acuña-CastroviejoD. DoerrierC. DayoubJ.C. LópezL.C. VenegasC. GarcíaJ.A. LópezA. VoltH. Luna-SánchezM. EscamesG. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis.J. Pineal Res.2015581344910.1111/jpi.1219125388914
     [Google Scholar]
  154. Fernández-GilB. MoneimA.E.A. OrtizF. ShenY.Q. Soto-MercadoV. Mendivil-PerezM. Guerra-LibreroA. Acuña-CastroviejoD. Molina-NavarroM.M. García-VerdugoJ.M. SayedR.K.A. FloridoJ. LunaJ.D. LópezL.C. EscamesG. Melatonin protects rats from radiotherapy-induced small intestine toxicity.PLoS One2017124e017447410.1371/journal.pone.017447428403142
     [Google Scholar]
  155. UthaiwatP. DaduangJ. PripremA. SettasatianC. Chio-SrichanS. LeeY.C. MahakunakornP. BoonsiriP. Topical melatonin niosome gel for the treatment of 5-fu-induced oral mucositis in mice.Curr. Drug Deliv.202118219921110.2174/156720181766620052515184832484102
     [Google Scholar]
  156. UthaiwatP. PripremA. Chio-SrichanS. SettasatianC. LeeY.C. MahakunakornP. BoonsiriP. LeelayuwatC. TippayawatP. PuthongkingP. DaduangJ. Oral administration of melatonin or succinyl melatonin niosome gel benefits 5-fu-induced small intestinal mucositis treatment in mice.AAPS PharmSciTech202122520010.1208/s12249‑021‑01941‑y34212283
     [Google Scholar]
  157. ElsabaghH.H. MoussaE. MahmoudS.A. ElsakaR.O. AbdelrahmanH. Efficacy of melatonin in prevention of radiation-induced oral mucositis: A randomized clinical trial.Oral Dis.202026356657210.1111/odi.1326531869853
     [Google Scholar]
  158. OnsengK. JohnsN.P. KhuayjarernpanishkT. SubongkotS. PripremA. HurstC. JohnsJ. Beneficial effects of adjuvant melatonin in minimizing oral mucositis complications in head and neck cancer patients receiving concurrent chemoradiation.J. Altern. Complement. Med.2017231295796310.1089/acm.2017.008128657801
     [Google Scholar]
  159. LozanoA. MarruecosJ. RubióJ. FarréN. Gómez-MillánJ. MoreraR. PlanasI. LanzuelaM. Vázquez-MasedoM.G. CascallarL. GiraltJ. EscamesG. ValentíV. GrimaP. BosserR. TarragóC. MesíaR. Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment.Clin. Transl. Oncol.20212391801181010.1007/s12094‑021‑02586‑w33738704
     [Google Scholar]
  160. O’ReillyM. MellotteG. RyanB. O’ConnorA. Gastrointestinal side effects of cancer treatments.Ther. Adv. Chronic Dis.202011204062232097035433294145
     [Google Scholar]
  161. SougiannisA.T. VanderVeenB.N. DavisJ.M. FanD. MurphyE.A. Understanding chemotherapy-induced intestinal mucositis and strategies to improve gut resilience.Am. J. Physiol. Gastrointest. Liver Physiol.20213205G712G71910.1152/ajpgi.00380.202033471628
     [Google Scholar]
  162. NajafiM. ChekiM. HassanzadehG. AminiP. ShabeebD. MusaA.E. Protection from radiation-induced damage in rat’s ileum and colon by combined regimens of melatonin and metformin: A histopathological study.Antiinflamm. Antiallergy Agents Med. Chem.202019218018910.2174/187152301866619071816192831438832
     [Google Scholar]
  163. AzarN.A. JavadiA. NajafiM. ShiraziA. TajabadiE. ShabeebD. MusaA.E. Evaluating radioprotection of rat’s jejunum by a combination of melatonin and metformin.Lett. Drug Des. Discov.202017447948410.2174/1570180816666190617153004
     [Google Scholar]
  164. ChekiM. NajafiM. HassanzadehG. AminiP. ShabeebD. MusaA. The radioprotective effect of combination of melatonin and metformin on rat duodenum damage induced by ionizing radiation: A histological study.Adv. Biomed. Res.201981515110.4103/abr.abr_68_1931516889
     [Google Scholar]
  165. TripathiA.M. KhanS. ChaudhuryN.K. Radiomitigation by melatonin in C57BL/6 mice: Possible implications as adjuvant in radiotherapy and chemotherapy.In Vivo20223631203122110.21873/invivo.1282035478105
     [Google Scholar]
  166. MusaA.E. ShabeebD. AlhilfiH.S.Q. Protective effect of melatonin against radiotherapy-induced small intestinal oxidative stress: Biochemical evaluation.Medicina201955630810.3390/medicina5506030831242652
     [Google Scholar]
  167. ComazzettoS. ShenB. MorrisonS.J. Niches that regulate stem cells and hematopoiesis in adult bone marrow.Dev. Cell202156131848186010.1016/j.devcel.2021.05.01834146467
     [Google Scholar]
  168. BatsivariA. HaltalliM.L.R. PassaroD. PosporiC. Lo CelsoC. BonnetD. Dynamic responses of the haematopoietic stem cell niche to diverse stresses.Nat. Cell Biol.202022171710.1038/s41556‑019‑0444‑931907409
     [Google Scholar]
  169. WangY. LiuL. PazhanisamyS.K. LiH. MengA. ZhouD. Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells.Free Radic. Biol. Med.201048234835610.1016/j.freeradbiomed.2009.11.00519925862
     [Google Scholar]
  170. WeyemiU. RedonC.E. AzizT. ChoudhuriR. MaedaD. ParekhP.R. BonnerM.Y. ArbiserJ.L. BonnerW.M. Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage.Radiat. Res.2015183326227010.1667/RR13799.125706776
     [Google Scholar]
  171. PazhanisamyS.K. LiH. WangY. Batinic-HaberleI. ZhouD. NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability.Mutagenesis201126343143510.1093/mutage/ger00121415439
     [Google Scholar]
  172. KocM. BuyukokurogluM.E. TaysiS. The effect of melatonin on peripheral blood cells during total body irradiation in rats.Biol. Pharm. Bull.200225565665710.1248/bpb.25.65612033509
     [Google Scholar]
  173. KumarA. ChoudharyS. KumarS. AdhikariJ.S. KapoorS. ChaudhuryN.K. Role of melatonin mediated G-CSF induction in hematopoietic system of gamma-irradiated mice.Life Sci.202228912019010.1016/j.lfs.2021.12019034883100
     [Google Scholar]
  174. AminiP. AshrafizadehM. MotevaseliE. NajafiM. ShiraziA. Mitigation of radiation-induced hematopoietic system injury by melatonin.Environ. Toxicol.202035881582110.1002/tox.2291732125094
     [Google Scholar]
  175. LiD. TianZ. TangW. ZhangJ. LuL. SunZ. ZhouZ. FanF. The protective effects of 5-methoxytryptamine-α-lipoic acid on ionizing radiation-induced hematopoietic injury.Int. J. Mol. Sci.201617693510.3390/ijms1706093527314327
     [Google Scholar]
  176. LissoniP. PaolorossiF. ArdizzoiaA. BarniS. ChilelliM. MancusoM. TanciniG. ContiA. MaestroniG.J.M. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state.J. Pineal Res.1997231151910.1111/j.1600‑079X.1997.tb00329.x9379341
     [Google Scholar]
  177. FabbrociniG. CameliN. RomanoM.C. MarianoM. PanarielloL. BiancaD. MonfrecolaG. Chemotherapy and skin reactions.J. Exp. Clin. Cancer Res.20123115010.1186/1756‑9966‑31‑5022640460
     [Google Scholar]
  178. WeiJ. MengL. HouX. QuC. WangB. XinY. JiangX. Radiation-induced skin reactions: Mechanism and treatment.Cancer Manag. Res.20181116717710.2147/CMAR.S18865530613164
     [Google Scholar]
  179. ShabeebD. NajafiM. MusaA.E. KeshavarzM. ShiraziA. HassanzadehG. HadianM.R. SamandariH. Biochemical and histopathological evaluation of the radioprotective effects of melatonin against gamma ray-induced skin damage.Curr. Radiopharm.2019121728110.2174/187447101266618112016325030465519
     [Google Scholar]
  180. Garcia-SeguraL.C. Garcia-SeguraJ.C. DelgadoD.C. RomeroM.N. SalgadoE.C. LlorensL.P. Compounded melatonin cream for the prevention and treatment of radiation dermatitis: A case report.Int. J. Pharm. Compd.20222616835081038
     [Google Scholar]
  181. Ben-DavidM.A. ElkayamR. GelernterI. PfefferR.M. Melatonin for prevention of breast radiation dermatitis: A phase II, prospective, double-blind randomized trial.Isr. Med. Assoc. J.2016183-418819227228641
     [Google Scholar]
  182. QuN. ItohM. SakabeK. Effects of chemotherapy and radiotherapy on spermatogenesis: The role of testicular immunology.Int. J. Mol. Sci.201920495710.3390/ijms2004095730813253
     [Google Scholar]
  183. WuS. YuK. LianZ. DengS. Molecular regulation of androgen receptors in major female reproductive system cancers.Int. J. Mol. Sci.20222314755610.3390/ijms2314755635886904
     [Google Scholar]
  184. DelessardM. SaulnierJ. RivesA. DumontL. RondaninoC. RivesN. Exposure to chemotherapy during childhood or adulthood and consequences on spermatogenesis and male fertility.Int. J. Mol. Sci.2020214145410.3390/ijms2104145432093393
     [Google Scholar]
  185. HoppeB.S. HowellR.M. LadraM. CahlonO. HamstraD.A. ConstineL.S. El NaqaI. LiA. CohenL.E. SkinnerR. KremerL. RonckersC.M. Spermatogenesis after testicular radiation exposure in children: Initial results from the pediatric normal tissue effects in the clinic (PENTEC) initiative.Int. J. Radiat. Oncol. Biol. Phys.20191051E631E63210.1016/j.ijrobp.2019.06.107831422803
     [Google Scholar]
  186. De FeliceF. MarchettiC. MaramponF. CascialliG. MuziiL. TomboliniV. Radiation effects on male fertility.Andrology2019712710.1111/andr.1256230411532
     [Google Scholar]
  187. KhanS. AdhikariJ.S. RizviM.A. ChaudhuryN.K. Radioprotective potential of melatonin against 60Co γ-ray-induced testicular injury in male C57BL/6 mice.J. Biomed. Sci.20152216110.1186/s12929‑015‑0156‑926205951
     [Google Scholar]
  188. TajabadiE. JavadiA. Ahmadi AzarN. NajafiM. ShiraziA. ShabeebD. Eleojo MusaA. Radioprotective effect of a combination of melatonin and metformin on mice spermatogenesis: A histological study.Int. J. Reprod. Biomed.202018121073108010.18502/ijrm.v18i12.802933426418
     [Google Scholar]
  189. KayaH. DelibasN. SerteserM. UlukayaE. ÖzkayaO. The effect of melatonin on lipid peroxidation during radiotherapy in female rats.Strahlenther. Onkol.1999175628528810.1007/BF0274358110392170
     [Google Scholar]
  190. ZhangJ. FangY. TangD. XuX. ZhuX. WuS. YuH. ChengH. LuoT. ShenQ. GaoY. MaC. LiuY. WeiZ. ChenX. TaoF. HeX. CaoY. Activation of MT1/MT2 to protect testes and leydig cells against cisplatin-induced oxidative stress through the SIRT1/Nrf2 signaling pathway.Cells20221110169010.3390/cells1110169035626727
     [Google Scholar]
  191. MoradiM. GoodarziN. FaramarziA. CheraghiH. HashemianA.H. JaliliC. Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis.Biomed. Pharmacother.202113811148110.1016/j.biopha.2021.11148133752059
     [Google Scholar]
  192. HardyS.J. KrullK.R. WefelJ.S. JanelsinsM. Cognitive changes in cancer survivors.Am. Soc. Clin. Oncol. Educ. Book2018383879580610.1200/EDBK_20117930231372
     [Google Scholar]
  193. AhlesT.A. Brain vulnerability to chemotherapy toxicities.Psychooncology201221111141114810.1002/pon.319623023994
     [Google Scholar]
  194. Greene-SchloesserD. RobbinsM.E. PeifferA.M. ShawE.G. WheelerK.T. ChanM.D. Radiation-induced brain injury: A review.Front. Oncol.201227310.3389/fonc.2012.0007322833841
     [Google Scholar]
  195. TurnquistC. HarrisB.T. HarrisC.C. Radiation-induced brain injury: Current concepts and therapeutic strategies targeting neuroinflammation.Neurooncol. Adv.202021vdaa05710.1093/noajnl/vdaa05732642709
     [Google Scholar]
  196. MotallebzadehE. TamehA.A. ZavarehS.A.T. FarhoodB. AliasgharzedehA. MohseniM. Neuroprotective effect of melatonin on radiation-induced oxidative stress and apoptosis in the brainstem of rats.J. Cell. Physiol.2020235118791879810.1002/jcp.2972232324264
     [Google Scholar]
  197. ÜndeğerÜ. GirayB. ZorluA.F. ÖgeK. BaçaranN. Protective effects of melatonin on the ionizing radiation induced DNA damage in the rat brain.Exp. Toxicol. Pathol.200455537938410.1078/0940‑2993‑0033215088639
     [Google Scholar]
  198. ErolF.S. TopsakalC. OzverenM.F. KaplanM. IlhanN. OzercanI.H. YildizO.G. Protective effects of melatonin and vitamin E in brain damage due to gamma radiation.Neurosurg. Rev.2004271656910.1007/s10143‑003‑0291‑812955582
     [Google Scholar]
  199. ZakriaM. AhmadN. Al KuryL.T. AlattarA. UddinZ. SirajS. UllahS. AlshamanR. KhanM.I. ShahF.A. RETRACTED: Melatonin rescues the mice brain against cisplatin-induced neurodegeneration, an insight into antioxidant and anti-inflammatory effects.Neurotoxicology20218711010.1016/j.neuro.2021.08.01034428482
     [Google Scholar]
  200. El-MissiryM.A. ShabanaS. GhazalaS.J. OthmanA.I. AmerM.E. Melatonin exerts a neuroprotective effect against γ-radiation-induced brain injury in the rat through the modulation of neurotransmitters, inflammatory cytokines, oxidative stress, and apoptosis.Environ. Sci. Pollut. Res. Int.20212824311083112110.1007/s11356‑021‑12951‑533598836
     [Google Scholar]
  201. MandaK. UenoM. AnzaiK. Cranial irradiation-induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: attenuation by melatonin pretreatment.J. Pineal Res.2009461717810.1111/j.1600‑079X.2008.00632.x18798786
     [Google Scholar]
  202. MandaK. AnzaiK. KumariS. BhatiaA.L. Melatonin attenuates radiation-induced learning deficit and brain oxidative stress in mice.Acta Neurobiol. Exp.2007671637017474322
     [Google Scholar]
  203. PalmerA.C.S. ZorteaM. SouzaA. SantosV. BiazúsJ.V. TorresI.L.S. FregniF. CaumoW. Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: A randomized, double-blind, placebo-controlled trial.PLoS One2020154e023137910.1371/journal.pone.023137932302347
     [Google Scholar]
  204. OunR. MoussaY.E. WheateN.J. The side effects of platinum-based chemotherapy drugs: A review for chemists.Dalton Trans.201847196645665310.1039/C8DT00838H29632935
     [Google Scholar]
  205. Koay, E.J.; Owen, D.; Das, P. Radiation-induced liver disease and modern radiotherapy.Semin. Radiat. Oncol.201828432133110.1016/j.semradonc.2018.06.00730309642
     [Google Scholar]
  206. TaysiS. KocM. BüyükokuroğluM.E. AltınkaynakK. ŞahinY.N. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver.J. Pineal Res.200334317317710.1034/j.1600‑079X.2003.00024.x12614476
     [Google Scholar]
  207. Hanedan UsluG. CanyilmazE. SerdarL. ErsözŞ. Protective effects of genistein and melatonin on mouse liver injury induced by whole-body ionising radiation.Mol. Clin. Oncol.201910226126630680205
     [Google Scholar]
  208. KarbownikM. ReiterR.J. QiW. GarciaJ.J. TanD.X. ManchesterL.C. Vijayalaxmi Protective effects of melatonin against oxidation of guanine bases in DNA and decreased microsomal membrane fluidity in rat liver induced by whole body ionizing radiation.Mol. Cell. Biochem.20002111/213714410.1023/A:100714853084511055556
     [Google Scholar]
  209. ShiraziA. MihandoostE. GhobadiG. MohseniM. Ghazi-KhansariM. Evaluation of radio-protective effect of melatonin on whole body irradiation induced liver tissue damage.Cell J.201314429229723577309
     [Google Scholar]
  210. KarakilçikA.Z. Bi̇ti̇renM. Zeri̇nM. Çeli̇kH. AksoyN. Melatonin increased vitamin C and antioxidant enzyme values in the plasma, heart, liver, and kidney of Adriamycin-treated rats.Turk. J. Biol.201539692593110.3906/biy‑1507‑79
     [Google Scholar]
  211. ShokrzadehM. AhmadiA. NaghshvarF. ChabraA. JafarinejhadM. Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice.Biomed Res Int.2014201447042510.1155/2014/470425
     [Google Scholar]
  212. JahovicN. ÇevikH. ŞehirliA.Ö. YeğenB.Ç. ŞenerG. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats.J. Pineal Res.200334428228710.1034/j.1600‑079X.2003.00043.x12662351
     [Google Scholar]
  213. MadhuP. ReddyK.P. ReddyP.S. Melatonin reduces oxidative stress and restores mitochondrial function in the liver of rats exposed to chemotherapeutics.J. Exp. Zool. A Ecol. Genet. Physiol.20153235301308
     [Google Scholar]
  214. MalyszkoJ. TesarovaP. CapassoG. CapassoA. The link between kidney disease and cancer: Complications and treatment.Lancet20203961024627728710.1016/S0140‑6736(20)30540‑732711803
     [Google Scholar]
  215. VarlottoJ.M. GersztenK. HeronD.E. ComerciJ. GautamS. SelvarajR. LalondeR. ChuraJ.C. The potential nephrotoxic effects of intensity modulated radiotherapy delivered to the para-aortic area of women with gynecologic malignancies: preliminary results.Am. J. Clin. Oncol.200629328128910.1097/01.coc.0000217828.95729.b516755182
     [Google Scholar]
  216. ZazuliZ. VijverbergS. SlobE. LiuG. CarletonB. VeltmanJ. BaasP. MasereeuwR. Maitland-van der ZeeA.H. Genetic variations and cisplatin nephrotoxicity: A systematic review.Front. Pharmacol.20189111110.3389/fphar.2018.0111130319427
     [Google Scholar]
  217. SantosM.L.C. BritoB.B. SilvaF.A.F. BotelhoA.C.S. MeloF.F. Nephrotoxicity in cancer treatment: An overview.World J. Clin. Oncol.202011419020410.5306/wjco.v11.i4.19032355641
     [Google Scholar]
  218. CanyilmazE. UsluG.H. BahatZ. KandazM. MunganS. HaciislamogluE. MenteseA. YoneyA. Comparison of the effects of melatonin and genistein on radiation-induced nephrotoxicity: Results of an experimental study.Biomed. Rep.201641455010.3892/br.2015.54726870332
     [Google Scholar]
  219. KucuktuluE. YavuzA.A. CobanogluU. YenilmezE. EminagaogluS. KarahanC. TopbasM. KucuktuluU. Protective effect of melatonin against radiation induced nephrotoxicity in rats.Asian Pac. J. Cancer Prev.20121384101410510.7314/APJCP.2012.13.8.410123098524
     [Google Scholar]
  220. AyzaM.A. ZewdieK.A. YigzawE.F. AyeleS.G. TesfayeB.A. TafereG.G. AbrhaM.G. Potential protective effects of antioxidants against cyclophosphamide-induced nephrotoxicity.Int. J. Nephrol.20222022509682510.1155/2022/5096825
     [Google Scholar]
  221. GoudarziM. KhodayarM.J. Hosseini TabatabaeiS.M.T. GhaznaviH. FatemiI. MehrzadiS. Pretreatment with melatonin protects against cyclophosphamide-induced oxidative stress and renal damage in mice.Fundam. Clin. Pharmacol.201731662563510.1111/fcp.1230328692163
     [Google Scholar]
  222. MandaK. BhatiaA.L. Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice.Cell Biol. Toxicol.200319636737210.1023/B:CBTO.0000013342.17370.1615015761
     [Google Scholar]
  223. MillerR.P. TadagavadiR.K. RameshG. ReevesW.B. Mechanisms of cisplatin nephrotoxicity.Toxins20102112490251810.3390/toxins211249022069563
     [Google Scholar]
  224. KilicU. KilicE. TuzcuZ. TuzcuM. OzercanI.H. YilmazO. SahinF. SahinK. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway.Nutr. Metab.2013101710.1186/1743‑7075‑10‑723311701
     [Google Scholar]
  225. WeiY. ZhangJ. YanX. PengX. XuS. ChangH. WangH. GaoY. Remarkable protective effects of nrf2-mediated antioxidant enzymes and tissue specificity in different skeletal muscles of daurian ground squirrels over the torpor-arousal cycle.Front. Physiol.201910144910.3389/fphys.2019.0144931824343
     [Google Scholar]
  226. FukutomiJ. FukudaA. FukudaS. HaraM. TeradaA. YoshidaM. Scavenging activity of indole compounds against cisplatin-induced reactive oxygen species.Life Sci.200680325425710.1016/j.lfs.2006.09.01117049361
     [Google Scholar]
  227. HaraM. YoshidaM. NishijimaH. YokosukaM. IigoM. Ohtani-KanekoR. ShimadaA. HasegawaT. AkamaY. HirataK. Melatonin, a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats.J. Pineal Res.200130312913810.1034/j.1600‑079X.2001.300301.x11316323
     [Google Scholar]
  228. ŞenerG. ŞatirogluH. KabasakalL. ArbakS. ÖnerS. ErcanF. Keyer-UysalM. The protective effect of melatonin on cisplatin nephrotoxicity.Fundam. Clin. Pharmacol.200014655356010.1111/j.1472‑8206.2000.tb00440.x11206705
     [Google Scholar]
  229. HrenákJ. ArendášováK. RajkovičováR. AziriováS. RepováK. KrajčírovičováK. CelecP. KamodyováN. BártaA. AdamcováM. PaulisL. ŠimkoF. Protective effect of captopril, olmesartan, melatonin and compound 21 on doxorubicin-induced nephrotoxicity in rats.Physiol. Res.201362S1S181S18910.33549/physiolres.93261424329698
     [Google Scholar]
  230. DzięgielP. SuderE. SurowiakP. JethonZ. RabczyńskiJ. JanuszewskaL. SopelM. ZabelM. Role of exogenous melatonin in reducing the nephrotoxic effect of daunorubicin and doxorubicin in the rat.J. Pineal Res.20023329510010.1034/j.1600‑079X.2002.02902.x12153443
     [Google Scholar]
  231. ÖzE. İlhanM.N. Effects of melatonin in reducing the toxic effects of doxorubicin.Mol. Cell. Biochem.20062861-2111510.1007/s11010‑005‑9003‑816652224
     [Google Scholar]
  232. AgapitoM.T. AntolínY. Del BrioM.T. López-BurilloS. PablosM.I. RecioJ.M. Protective effect of melatonin against adriamycin toxicity in the rat.J. Pineal Res.2001311233010.1034/j.1600‑079X.2001.310104.x11485001
     [Google Scholar]
  233. MontillaP.L. TúnezI.F. AguedaC.M. GascónF.L. López SoriaJ.V. Protective role of melatonin and retinol palmitate in oxidative stress and hyperlipidemic nephropathy induced by adriamycin in rats.J. Pineal Res.1998252869310.1111/j.1600‑079X.1998.tb00544.x9755029
     [Google Scholar]
  234. AbrahamP. KolliV.K. RabiS. Melatonin attenuates methotrexate-induced oxidative stress and renal damage in rats.Cell Biochem. Funct.201028542643310.1002/cbf.167620589739
     [Google Scholar]
  235. OguzE. KocarslanS. TaburS. SezenH. YilmazZ. AksoyN. Effects of lycopene alone or combined with melatonin on methotrexate-induced nephrotoxicity in rats.Asian Pac. J. Cancer Prev.201516146061606610.7314/APJCP.2015.16.14.606126320496
     [Google Scholar]
  236. LeeI.C. KimS.H. LeeS.M. BaekH.S. MoonC. KimS.H. ParkS.C. KimH.C. KimJ.C. Melatonin attenuates gentamicin-induced nephrotoxicity and oxidative stress in rats.Arch. Toxicol.201286101527153610.1007/s00204‑012‑0849‑822526374
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673262122231011172100
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Melatonin in Chemo/Radiation Therapy; Implications for Normal Tissues Sparing and Tumor Suppression: An Updated Review
Curr. Med. Chem. 32, 511 (2025); https://doi.org/10.2174/0109298673262122231011172100
/content/journals/cmc/10.2174/0109298673262122231011172100
/content/journals/cmc/10.2174/0109298673262122231011172100
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  • Article Type:     Review Article
Keyword(s): cancer resistance; chemotherapy; Melatonin; normal tissue; radiotherapy; toxicity

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