The Role of Melatonin in Colorectal Cancer

  • Shahrokh Iravani
  • Pegah Eslami
  • Arash Dooghaie Moghadam
  • Bobak Moazzami
  • Azim Mehrvar
  • Mahmood Reza Hashemi
  • Fariborz Mansour-GhanaeiEmail author
  • Alireza Mansour-Ghanaei
  • Keivan Majidzadeh-AEmail author
Review Article


The prevalence and mortality rate of colorectal cancer have been dramatically rising globally. Currently, colorectal cancer is emerging as the fourth leading cause of death and the third most common malignancy worldwide. The major drawback in colorectal cancer treatment is related to severe adverse events of both chemotherapy and radiation therapy that lead to toxicity and inflammation. Recently, melatonin as an antioxidant, immune-stimulant, and antimutagenic agent has been noticed. Different studies worked on the molecular role of melatonin on carcinogenesis progression. Overall, the anticancer activity of melatonin, combined with its actions via multiple signaling pathways, is considered hugely exciting to use this drug as a possible treatment strategy to cure cancer. Apart from its anticancer potential, this drug has shown to induce modulation of chemotherapy toxicity and improving its therapeutic efficacy. The present review aimed to discuss the possible role of melatonin usage in management of colorectal cancer.


Colorectal cancer Melatonin Pineal hormones Chemotherapy 


Compliance with Ethical Standards

This study was conducted in compliance with the provisions of the Helsinki Declaration.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Research. 2006;66(20):9789–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Su SC, Hsieh MJ, Yang WE, Chung WH, Reiter RJ, Yang SF. Cancer metastasis: mechanisms of inhibition by melatonin. Journal of Pineal Research. 2017;62(1):e12370.CrossRefGoogle Scholar
  3. 3.
    Abrial C, Kwiatkowski F, Chevrier R, Gachon F, Cure H, Chollet P. Therapeutic potential of melatonin in cancer treatment. Pathologie-biologie. 2005;53(5):265–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Chiru AZ, Popescu C, Gheorghe D. Melatonin and cancer. Journal of Medicine and Life. 2014;7(3):373.Google Scholar
  5. 5.
    Carpentieri A, De Barboza GD, Areco V, López MP, De Talamoni NT. New perspectives in melatonin uses. Pharmacological Research. 2012;65(4):437–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Sánchez-Barceló E, Mediavilla M, Tan D, Reiter RJ. Clinical uses of melatonin: evaluation of human trials. Current Medicinal Chemistry. 2010;17(19):2070–95.PubMedCrossRefGoogle Scholar
  7. 7.
    Blask DE. Melatonin, sleep disturbance and cancer risk. Sleep Medicine Reviews. 2009;13(4):257–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang Y-m, B-z J, Ai F, C-h D, Lu Y-z, Dong T-f, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemotherapy and Pharmacology. 2012;69(5):1213–20.PubMedCrossRefGoogle Scholar
  9. 9.
    Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integrative Cancer Therapies. 2008;7(3):189–203.PubMedCrossRefGoogle Scholar
  10. 10.
    Safiri S, Sepanlou SG, Ikuta KS, Bisignano C, Salimzadeh H, Delavari A, et al. The global, regional, and national burden of colorectal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet Gastroenterology & Hepatology. 2019. Scholar
  11. 11.
    Hong Y, Won J, Lee Y, Lee S, Park K, Chang KT, et al. Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. Journal of Pineal Research. 2014;56(3):264–74.PubMedCrossRefGoogle Scholar
  12. 12.
    Nikbakht HA, Sahraian S, Ghaem H, Javadi A, Janfada M, Hassanipour S, et al. Trends in mortality rates for gastrointestinal cancers in Fars Province, Iran (2005-2015). Journal of Gastrointestinal Cancer. 2019:1–7.
  13. 13.
    Rafiemanesh H, Pakzad R, Abedi M, Kor Y, Moludi J, Towhidi F, et al. Colorectal cancer in Iran: epidemiology and morphology trends. EXCLI journal. 2016;15:738–44. Scholar
  14. 14.
    Gandomani HS, Aghajani M, Mohammadian-Hafshejani A, Tarazoj AA, Pouyesh V, Salehiniya H. Colorectal cancer in the world: incidence, mortality and risk factors. Biomedical Research and Therapy. 2017;4(10):1656–75.CrossRefGoogle Scholar
  15. 15.
    Rafiemanesh H, Mohammadian-Hafshejani A, Ghoncheh M, Sepehri Z, Shamlou R, Salehiniya H, et al. Incidence and mortality of colorectal cancer and relationships with the human development index across the world. Asian Pacific Journal of Cancer Prevention. 2016;17(5):2465–73.PubMedGoogle Scholar
  16. 16.
    Nikbakht HA, Shokri-Shirvani J, Ashrafian-Amiri H, Ghaem H, Jafarnia A, Alijanpour S, et al. The first screening program for colorectal cancer in the North of Iran. Journal of Gastrointestinal Cancer. 2019:1–7.
  17. 17.
    Tfaily MA, Naamani D, Kassir A, Sleiman S, Ouattara M, Moacdieh MP, et al. Awareness of colorectal cancer and attitudes towards its screening guidelines in Lebanon. Annals of Global Health. 2019;85(1). Scholar
  18. 18.
    Ramdzan AR, Abd Rahim MA, Mohamad Zaki A, Zaidun Z, Mohammed Nawi A. Diagnostic accuracy of FOBT and colorectal cancer genetic testing: a systematic review & meta-analysis. Annals of Global Health. 2019;85(1).
  19. 19.
    Croft B, Reed M, Patrick C, Kovacevich N, Voutsadakis IA. Diabetes, obesity, and the metabolic syndrome as prognostic factors in stages I to III colorectal cancer patients. Journal of Gastrointestinal Cancer. 2019;50(2):221–9. Scholar
  20. 20.
    Farhood B, Goradel N, Mortezaee K, Khanlarkhani N, Salehi E, Nashtaei M, et al. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clinical and Translational Oncology. 2019;21(3):268–79.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Najafi M, Shirazi A, Motevaseli E, Rezaeyan A, Salajegheh A, Rezapoor S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology. 2017;25(4):403–13.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Cutando A, Lopez-Valverde A, Arias-Santiago S, De Vicente J, DE DIEGO RG. Role of melatonin in cancer treatment. Anticancer Research. 2012;32(7):2747–53.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Asghari MH, Ghobadi E, Moloudizargari M, Fallah M, Abdollahi M. Does the use of melatonin overcome drug resistance in cancer chemotherapy? Life Sciences. 2018;196:143–55.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Kos-Kudla B, Ostrowska Z, Kozlowski A, Marek B, Ciesielska-Kopacz N, Kudla M, et al. Circadian rhythm of melatonin in patients with colorectal carcinoma. Neuroendocrinology Letters. 2002;23(3):239–42.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiology and Prevention Biomarkers. 2016;25(1):16–27.CrossRefGoogle Scholar
  26. 26.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. 2010;127(12):2893–917.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015;136(5):E359–86.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncology. 2017;3(4):524–48.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2010;116(3):544–73.CrossRefGoogle Scholar
  30. 30.
    Posadzki PP, Bajpai R, Kyaw BM, Roberts NJ, Brzezinski A, Christopoulos GI, et al. Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action. BMC Medicine. 2018;16(1):18–8.
  31. 31.
    Wang Y, Wang P, Zheng X, Du X. Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis. OncoTargets and therapy. 2018;11:7895–908. Scholar
  32. 32.
    Anisimov VN, Popovich IG, Shtylik AV, Zabezhinski MA, Ben-Huh H, Gurevich P, et al. Melatonin and colon carcinogenesis. III. Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1,2-dimethylhydrazine in rats. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie. 2000;52(1):71–6. Scholar
  33. 33.
    Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine. 2005;27(2):179–88. Scholar
  34. 34.
    Gilad E, Laufer M, Matzkin H, Zisapel N. Melatonin receptors in PC3 human prostate tumor cells. Journal of Pineal Research. 1999;26(4):211–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Hu DN, McCormick SA, Roberts JE. Effects of melatonin, its precursors and derivatives on the growth of cultured human uveal melanoma cells. Melanoma Research. 1998;8(3):205–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Kanishi Y, Kobayashi Y, Noda S, Ishizuka B, Saito K. Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines. Journal of Pineal Research. 2000;28(4):227–33.PubMedCrossRefGoogle Scholar
  37. 37.
    Karbownik M, Lewinski A, Reiter RJ. Anticarcinogenic actions of melatonin which involve antioxidative processes: comparison with other antioxidants. The International Journal of Biochemistry & Cell Biology. 2001;33(8):735–53.CrossRefGoogle Scholar
  38. 38.
    Klaunig JE, Xu Y, Isenberg JS, Bachowski S, Kolaja KL, Jiang J, et al. The role of oxidative stress in chemical carcinogenesis. Environmental Health Perspectives. 1998;106(Suppl 1):289–95. Scholar
  39. 39.
    van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010;33(12):1605–14. Scholar
  40. 40.
    Cos S, Gonzalez A, Martinez-Campa C, Mediavilla MD, Alonso-Gonzalez C, Sanchez-Barcelo EJ. Melatonin as a selective estrogen enzyme modulator. Current Cancer Drug Targets. 2008;8(8):691–702.PubMedCrossRefGoogle Scholar
  41. 41.
    Vijayalaxmi TCR Jr, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002;20(10):2575–601. Scholar
  42. 42.
    Sanchez-Barcelo EJ, Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C. Melatonin-estrogen interactions in breast cancer. Journal of Pineal Research. 2005;38(4):217–22. Scholar
  43. 43.
    Shafabakhsh R, Reiter RJ, Davoodabadi A, Asemi Z. Melatonin as a potential inhibitor of colorectal cancer: molecular mechanisms. Journal of Cellular Biochemistry. 2019;120(8):12216–23. Scholar
  44. 44.
    Proietti S, Cucina A, Reiter RJ, Bizzarri M. Molecular mechanisms of melatonin’s inhibitory actions on breast cancers. Cellular and Molecular Life Sciences: CMLS. 2013;70(12):2139–57. Scholar
  45. 45.
    Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L, Reiter RJ. Basic mechanisms involved in the anti-cancer effects of melatonin. Current Medicinal Chemistry. 2010;17(36):4462–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Bojková B, Kubatka P, Qaradakhi T, Zulli A, Kajo K. Melatonin may increase anticancer potential of pleiotropic drugs. International Journal of Molecular Sciences. 2018;19(12):3910. Scholar
  47. 47.
    Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ. Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opinion on Investigational Drugs. 2012;21(6):819–31. Scholar
  48. 48.
    Lissoni P. Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathologie-biologie. 2007;55(3-4):201–4. Scholar
  49. 49.
    Lissoni P, Paolorossi F, Tancini G, Barni S, Ardizzoia A, Brivio F, et al. Is there a role for melatonin in the treatment of neoplastic cachexia? European Journal of Cancer. 1996;32(8):1340–3.CrossRefGoogle Scholar
  50. 50.
    Dhanapal R, Saraswathi T, Govind RN. Cancer cachexia. Journal of oral and maxillofacial pathology: JOMFP. 2011;15(3):257–60.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Skipworth RJ, Stewart GD, Dejong CH, Preston T, Fearon KC. Pathophysiology of cancer cachexia: much more than host–tumour interaction? Clinical Nutrition. 2007;26(6):667–76.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Persson C, Glimelius B, Rönnelid J, Nygren P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition. 2005;21(2):170–8.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Xin Z, Jiang S, Jiang P, Yan X, Fan C, Di S, et al. Melatonin as a treatment for gastrointestinal cancer: a review. Journal of Pineal Research. 2015;58(4):375–87.PubMedCrossRefGoogle Scholar
  54. 54.
    Reiter RJ, Tan D, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: reducing the toxicity and increasing the efficacy of drugs. Journal of Pharmacy and Pharmacology. 2002;54(10):1299–321.PubMedCrossRefGoogle Scholar
  55. 55.
    Siu SW, Lau KW, Tam PC, Shiu SY. Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. The Prostate. 2002;52(2):106–22.PubMedCrossRefGoogle Scholar
  56. 56.
    Vician M, Zeman M, Herichova I, Jurani M, BlaŽiČek P, Matis P. Melatonin content in plasma and large intestine of patients with colorectal carcinoma before and after surgery. Journal of Pineal Research. 1999;27(3):164–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Srinivasan V, R. Pandi-Perumal S, Brzezinski A, P Bhatnagar K, P Cardinali D (2011) Melatonin, immune function and cancer. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 5 (2):109-123Google Scholar
  58. 58.
    Khoory R, Stemme D. Plasma melatonin levels in patients suffering from colorectal carcinoma. Journal of Pineal Research. 1988;5(3):251–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Frajacomo F, de Paula GW, Fernandes C, Garcia SB, Kannen V. Pineal gland function is required for colon antipreneoplastic effects of physical exercise in rats. Scandinavian Journal of Medicine & Science in Sports. 2015;25(5):e451–8.CrossRefGoogle Scholar
  60. 60.
    Sookprasert A, Johns NP, Phunmanee A, Pongthai P, Cheawchanwattana A, Johns J, et al. Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial. Anticancer Research. 2014;34(12):7327–37.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Zetner D, Andersen L, Rosenberg J. Melatonin as protection against radiation injury: a systematic review. Drug research. 2016;66(06):281–96.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Cerea G, Vaghi M, Ardizzoia A, Villa S, Bucovec R, Mengo S, et al. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Research. 2003;23(2C):1951–4.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Raghavendra V, Kulkarni SK. Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis. Brain Research. 2000;860(1-2):112–8.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. Journal of Clinical Oncology. 2013;31(10):1271.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shahrokh Iravani
    • 1
    • 2
  • Pegah Eslami
    • 3
  • Arash Dooghaie Moghadam
    • 3
  • Bobak Moazzami
    • 3
  • Azim Mehrvar
    • 1
  • Mahmood Reza Hashemi
    • 2
  • Fariborz Mansour-Ghanaei
    • 4
    Email author
  • Alireza Mansour-Ghanaei
    • 4
  • Keivan Majidzadeh-A
    • 1
    • 5
    Email author
  1. 1.AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC)AJA University of Medical SciencesTehranIran
  2. 2.Gastroenterology and Hepatobiliary Research CenterAJA University of Medical SciencesTehranIran
  3. 3.Liver Transplantation Research CenterTehran University of Medical SciencesTehranIran
  4. 4.Gastrointestinal and Liver Diseases Research CenterGuilan University of Medical SciencesRashtIran
  5. 5.Genetics Department, Breast Cancer Research CenterMotamed Cancer Institute, ACECRTehranIran

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