Skip to main content

Advertisement

SpringerLink
Log in

Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

The last four decades, we assist to an increasing scientific interest on melatonin, a circadian hormone, a metabolic regulator which influences not only plants’ metabolism and their defense against pathogens but mostly the animals and humans’ metabolic pathways, their response to circadian disruption, stress and burnout syndrome. In humans, as a hormonal regulator, produced in the pineal grand as well in mitochondria, melatonin is involved in different, complex intracellular signaling pathways, with antioxidant and immune stimulating effects, proving to act as a circadian synchronizer, as a preventive and therapeutic agent in many degenerative diseases, and especially in hormone-dependent cancers. Preclinical or clinical studies showed recently the mechanisms involved in regulating the cellular activity, its role in aging and circadian disturbances and impact on degenerative diseases. Melatonin proved to have an anti-inflammatory, antiapoptotic and powerful antioxidant effect by subtle mechanisms in mitochondrial metabolic pathways. This overview includes recent and relevant literature data related to the impact of endogenous and exogeneous melatonin on the prevention of cancer progression and treatment of various degenerative diseases. Metabolomics, an emerging new omics’ technology, based on high performance liquid chromatography coupled with mass spectrometry is presented as an encouraging technique to fingerprint and realize a precise evaluation and monitoring of the turnover of melatonin and its metabolites in different pathological circumstances.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH. Daily rhythm in human urinary melatonin. Science. 1975;187(4172):169–71.

    CAS  PubMed  Google Scholar 

  2. Lewis A. Melatonin and the biological clock. McGraw-Hill 1999. ISBN 978-0-87983-734-1.

  3. Salehi B, Sharopov F, Tsouh Fokou PV, Kobylinska A, de Jonge L, Tadio K, Sharifi-rad J, Posmyk MM, Martorell M, Martins N, Iriti M. Melatonin in medicinal and food plants: occurrence, bioavailability, and health potential for humans. Cells. 2019;8(7):681–98.

    CAS  PubMed Central  Google Scholar 

  4. Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes. J Pineal Res. 2013;54:127–38.

    CAS  PubMed  Google Scholar 

  5. Hardeland R. Melatonin in plants and other phototrophs: advances and gaps concerning the diversity of functions. J Exp Botany. 2015;66:627–46.

    CAS  Google Scholar 

  6. Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Reiter RJ. Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int. 1995;35:627–34.

    CAS  Google Scholar 

  7. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocrine Rev. 1991;12:151–80.

    CAS  Google Scholar 

  8. Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas. Cell Mol Life Sci. 2017;74:3863–81.

    CAS  PubMed  Google Scholar 

  9. Zhao D, Yu Y, Shen Y, et al. Melatonin synthesis and function: evolutionary history in animals and plants. Front Endocrinol (Lausanne). 2019;10:249.

    Google Scholar 

  10. Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ. Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. J Exp Botany. 2012;63:577–97.

    CAS  Google Scholar 

  11. Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ. Phytomelatonin: a review. J Exp Botany. 2009;60:57–69.

    CAS  Google Scholar 

  12. Nawaz MA, Huang Y, Bie Z, Ahmed W, Russel J, Reiter RJ, Niu M, Hameed S. Melatonin: current status and future perspectives in plant science. Front Plant Sci. 2016;6:1230–41.

    PubMed  PubMed Central  Google Scholar 

  13. Reiter RJ, Tan DX, Zhou Z, Cruz MH, Fuentes-Broto L, Galano A. Phytomelatonin: assisting plants to survive and thrive. Molecules. 2015;20:7396–437.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Arnao MB, Hernández-Ruiz J. The physiological function of melatonin in plants. Plant Signal Behav. 2006;1:89–95.

    PubMed  PubMed Central  Google Scholar 

  15. Arnao MB, Hernández-Ruiz J. Functions of melatonin in plants: a review. J Pineal Res. 2015;59:133–50.

    CAS  PubMed  Google Scholar 

  16. Boutin JA, Audinot V, Ferry G, Delagrange P. Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci. 2005;26:412–9.

    CAS  PubMed  Google Scholar 

  17. Zhu Y, Gao H, Lu MX, Hao CY, Pu ZQ, Guo MJ, Hou DR, Chen LY, Huang X. Melatonin-nitric oxide crosstalk and their roles in the redox network in plants. Int J Mol Sci. 2019;20:6200.

    CAS  PubMed Central  Google Scholar 

  18. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007;42:28–42.

    CAS  PubMed  Google Scholar 

  19. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005;27:119–30.

    CAS  PubMed  Google Scholar 

  20. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61:253–78.

    CAS  PubMed  Google Scholar 

  21. Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab. 1993;77:838–41.

    CAS  PubMed  Google Scholar 

  22. Sae-Teaw M, Johns J, Johns NP, Subongkot S. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers. J Pineal Res. 2013;55:58–64.

    CAS  PubMed  Google Scholar 

  23. Yilmaz C, Gokmen V. Neuroactive compounds in foods: occurrence, mechanism and potential health effects. Food Res Int. 2020;128:108744.

    CAS  PubMed  Google Scholar 

  24. Pereira N, Naufel MF, Ribeiro EB, Tufik S, Hachul H. Influence of dietary sources of melatonin on sleep quality: A review. J Food Sci. 2020;85:5–13.

    CAS  PubMed  Google Scholar 

  25. Hardeland R. Melatonin, hormone of darkness and more – occurrence, control mechanisms, actions and bioactive metabolites. Cell Mol Life Sci. 2008;65:2001–18.

    CAS  PubMed  Google Scholar 

  26. Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175:3190–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A. A review of melatonin, its receptors and drugs. Eurasian J Med. 2016;48:135–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR. Melatonin, a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci. 1994;738:419–20.

    CAS  PubMed  Google Scholar 

  29. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci. 1994;55:271–6.

    Google Scholar 

  30. Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59:403–19.

    CAS  PubMed  Google Scholar 

  31. Peyrot F, Ducrocq C. Potential role of tryptophan derivatives in stress responses characterized by the generation of reactive oxygen and nitrogen species. J Pineal Res. 2008;45:235–46.

    CAS  PubMed  Google Scholar 

  32. Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX. Melatonin combats molecular terrorism at the mitochondrial level. Interdisc Toxicol. 2008;1:137–49.

    Google Scholar 

  33. Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A. Melatonin and human mitochondrial diseases. J Res Med Sci. 2017;22:2–10.

    PubMed  PubMed Central  Google Scholar 

  34. Reiter RJ, Paredes SD, Manchester LC, Tan DX. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol. 2009;44:175–200.

    CAS  PubMed  Google Scholar 

  35. Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15:434–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Shirazi A, Ghobadi G, Ghazi-Khansari M. A radiobiological review on melatonin: a novel radioprotector. J Rad Res. 2007;48:263–72.

    CAS  Google Scholar 

  37. Meltz ML, Reiter RJ, Herman TS, Kumar KS. Melatonin and protection from whole-body irradiation: survival studies in mice. Mutation Res. 1999;425:21–7.

    PubMed  Google Scholar 

  38. Reiter RJ, Herman TS, Meltz ML. Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers. Mutation Res. 1996;371:221–8.

    PubMed  Google Scholar 

  39. Reiter RJ, Herman TS, Meltz ML. Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes. Mutation Res. 1998;397:203–8.

    PubMed  Google Scholar 

  40. Schomerus C, Korf HW. Mechanisms regulating melatonin synthesis in the mammalian pineal organ. Ann N Y Acad Sci. 2005;1057:372–83.

    CAS  PubMed  Google Scholar 

  41. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on melatonin receptors: IUPHA review 20. Br J Pharmacol. 2016;173:2702–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, Pinton P. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 2019;10:317–26.

    PubMed  PubMed Central  Google Scholar 

  43. Liu L, Labani N, Cecon E, Jockers R. Melatonin target proteins: too many or not enough? Front Endocrinol. 2019;10:791.

    Google Scholar 

  44. Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine. 2005;27:189–200.

    CAS  PubMed  Google Scholar 

  45. Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernández-Montesinos R, Guerrero JM, Pozo D. The modulatory role of melatonin on immune responsiveness. Curr Opinion Invest Drugs. 2006;7:423–31.

    CAS  Google Scholar 

  46. Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs. 2001;10:467–76.

    CAS  PubMed  Google Scholar 

  47. Armstrong SM, Redman JR. Melatonin: a chronobiotic with anti-aging properties? Med Hypotheses. 1991;34:300–9.

    CAS  PubMed  Google Scholar 

  48. Reiter RJ. The melatonin rhythm: both a clock and a calendar. Experintia. 1993;49:654–64.

    CAS  Google Scholar 

  49. Kayumov L, Casper RF, Hawa RJ, Perelman B, Chung SA, Sokalsk S, Shapiro CM. Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work. J Clin Endocrinol Metab. 2005;90:2755–61.

    CAS  PubMed  Google Scholar 

  50. Hardeland R. Melatonin in aging and disease:multiple consequences of reduced secretion, options and limits of treatment. Aging Dis. 2012;3:194–225.

    PubMed  Google Scholar 

  51. Hardeland R, Madrid JA, Tan DX, Reiter RJ. Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res. 2012;52:139–66.

    CAS  PubMed  Google Scholar 

  52. Abbott SM, Malkani RG, Zee PC. Circadian disruption and human health: A bidirectional relationship. Eur J Neurosci. 2020;51:567–83.

    PubMed  Google Scholar 

  53. Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ. Management of insomnia disorder. AHRQ Comparative Effectiveness Reviews. No. 159 2015.

  54. Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders (PDF). Sleep Med Reviews. 2017;34:10–22.

    Google Scholar 

  55. Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis (PDF). Arch Disease Childhood. 2018;103:1155–62.

    Google Scholar 

  56. Matheson E, Hainer BL. Insomnia: pharmacologic therapy. Am Fam Physician. 2017;96:29–35.

    PubMed  Google Scholar 

  57. Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, Ruotsalainen JH. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. Cochrane Database Syst Rev. 2014;8:CD009776.

    Google Scholar 

  58. Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: A systematic review. CNS Drugs. 2019;33:1167–86.

    PubMed  Google Scholar 

  59. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klasen TP, Baker B. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. Br Med J. 2006;332:385–93.

    CAS  Google Scholar 

  60. Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disorders. 2006;36:741–52.

    CAS  Google Scholar 

  61. Jonsdottir IH, Dahlman AS. Endocrine and immunological aspects of burnout: a narrative review. Eur J Endocrinol. 2019;180:R147–58.

    CAS  PubMed  Google Scholar 

  62. Bendz LM, Scates AC. Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder. Ann Pharmacotherapy. 2010;44:185–91.

    CAS  Google Scholar 

  63. Valdés-Tovar M, Estrada-Reyes R, Solís-Chagoyán H, Argueta J, Dorantes-Barrón AM, Quero-Chávez D, Cruz-Garduno R, Cercos MG, Trueta C, Oikawa-Sala J, Dubocovich ML, Benitez-King G. Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression. Br J Pharmacol. 2018;175:3200–8.

    PubMed  PubMed Central  Google Scholar 

  64. Bonnefont-Rousselot D, Collin F. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology. 2010;278:55–67.

    CAS  PubMed  Google Scholar 

  65. Reiter RJ, Tan DX, Korkmaz A, Erren TC, Piekarski C, Tamura H, Manchester LC. Light at night, chronodisruption, melatonin suppression, and cancer risk: a review. Crit Rev Oncol. 2007;13:303–28.

    Google Scholar 

  66. Chuffa L, Seiva F, Cucielo M, Silveira H, Reiter RJ, Lupi LA. Clock genes and the role of melatonin in cancer cells: an overview. Melatonin Res. 2019;2:133–57.

    Google Scholar 

  67. Tan D-X. Reiter RJ mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Res. 2019;2:44–66.

    Google Scholar 

  68. Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K. Melatonin, a full service anticancer agent: inhibition of initiation, progression and metastasis. Int J Mol Sci. 2017;18:4.

    Google Scholar 

  69. Reiter RJ, Sharma R, Ma Q, Rorsales-Corral S, Chuffa LGD. Melatonin inhibits Warburg-dependent cancer by redirecting glucose oxidation to the mitochondria: a mechanistic hypothesis. Cell Mol Life Sci. 2020:1–12.

  70. Ren W, Liu G, Chen S, Yin J, Wang J, Tan B, Wu G, Bazer FW, Peng Y, Tiejun L. Melatonin signaling in T cells: functions and applications. J Pineal Res. 2017;62:e12394.

    Google Scholar 

  71. Liu Z, Yu K, Zheng J, Lin H, Zhao Q, Zhang X, Feng W, Wang L, Xu J, Xie D, Zuo Z-X, Liu Z-X, Zheng Q. Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers. Cancer Med. 2019;8:1710–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Mortezaee K, Potes Y, Mirtavoos-Mahyari H, Motevaseli E, Shabeeb D, Musa AE, Najafi M, Farhood B. Boosting immune system against cancer by melatonin: A mechanistic viewpoint. Life Sci. 2019;238:116960.

    CAS  PubMed  Google Scholar 

  73. Boga JA, Caballero B, Potes Y, Perez-Martinez Z, Reiter RJ, Vega-Naredo I, Coto-Montes A. Therapeutic potential of melatonin related to its role as an autophagy regulator: A review. J Pineal Res. 2019;66:e12534.

    PubMed  Google Scholar 

  74. Giudice A, Crispo A, Grimaldi M, et al. The effect of light exposure at night (LAN) on carcinogenesis via decreased nocturnal melatonin synthesis. Molecules. 2018;23:E1308.

    PubMed  Google Scholar 

  75. Garaulet M, Qian J, Florez JC, Arendt J, Saxena R, Scheer FAJL. Melatonin effects on glucose metabolism: time to unlock the controversy. Trends Endocrinol Metab. 2020;31(3):192–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tamtaji OR, Reiter RJ, Alipoor R, Dadgostar E, Kouchaki E, Asemi Z. Melatonin and Parkinson disease: current status and future perspectives for molecular mechanisms. Cell Mol Neurobiol. 2020;40:15–23.

    PubMed  Google Scholar 

  77. Shukla M, Chinchalongporn V, Govitrapong P, Reiter RJ. The role of melatonin in targeting cell signaling pathways in neurodegeneration. Ann N Y Acad Sci. 2019;1443:75–96.

    PubMed  Google Scholar 

  78. Zhang TW, Li ZF, Dong J, Jiang LB. The circadian rhythm in intervertebral disc degeneration: an autophagy connection. Exp Mol Med. 2020;52:31–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ma Q, Reiter RJ, Chen YD. Role of melatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis. 2020;23:91–104.

    PubMed  Google Scholar 

  80. Bartsch C, Bartsch H, Fluchter SH, Lippert TH. Depleted pineal melatonin production in primary breast and prostate cancer is connected with circadian disturbances: possible role of melatonin for synchronization of circadian rhythmicity. In: Touitou Y, Arendt J, Pevet P, editors. Melatonin and the pineal gland - from basic science to clinical application. Elsevier: New York; 1993. p. 311–6.

    Google Scholar 

  81. Kos-Kudla B, Ostrowska Z, Kozlowski A, Marek BM, Ciesielska-Kopacz N, Kudla M, Kajdaniuk D, Strzelczyk J, Staszewicz P. Circadian rhythm of melatonin in patients with colorectal carcinoma. Neuroendocrinol Lett. 2002;23:239–42.

    CAS  PubMed  Google Scholar 

  82. Iravani S, Eslami P, Moghadam AD, Moazzami B, Mehrvar A, Hashemi MR, Mansour-Ghanaei F, Mansour-Ghanaei A, Majidzadeh AK. The role of melatonin in colorectal cancer. J Gastrointest Canc. 2019; https://doi.org/10.1007/s12029-019-00336-4.

  83. Gil-Martin E, Egea J, Reiter RJ, Romero A. The emergence of melatonin in oncology: focus on colorectal cancer. Med Res Rev. 2019;39:2239–85.

    PubMed  Google Scholar 

  84. Aghazadeh-Attari M, Mohammadzadeh M, Mostavafi S, Mihanfar A, Ghazizadeh S, Sadighparvar S, Gholamzadeh S, Majidinia M, Yousefi B. Melatonin: an important anticancer agent in colorectal cancer. J Cell Physiol. 2020;235:804–17.

    Google Scholar 

  85. Karasek M, Carillo-Vico A, Guerrero JM, Winczyk K, Pawlikowsky M. Expression of melatonin MT(1) and MT(2) receptors, and ROR alpha(1) receptor in transposable murine Colon 38 cancer. Neuroendocrinol Lett. 2002;23:55–60.

    CAS  PubMed  Google Scholar 

  86. Fathizadeh H, Mirzaei H, Asemi Z. Melatonin: an anti-tumor agent for osteosarcoma. Cancer Cell Int. 2019;19:319.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Neamati F, Asemi Z. The effects of melatonin on signaling pathways and molecules involved in glioma. Fund Clin Pharmacol. 2020; https://doi.org/10.1111/fcp.12538.

  88. Mojaverrostami S, Asghari N, Khamisabadi M, Khoei HH. The role of melatonin in polycystic ovary syndrome: A review. Int J Reprod Biomed. 2019;17:865–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Rimler A, Lupowitz Z, Zisapel N. Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells. Neuroendocrinol Lett. 2002;23:45–9.

    CAS  PubMed  Google Scholar 

  90. Kubo T, Ozasa K, Mikami E, Wakai K, Fujino Y, Watanabe Y, Miki T, Nakao M, Hayashi K, Suzuki K, Mori M, Washio M, Sakauchi F, Ito Y, Yoshimura T, Tamakoshi A. Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study. Am J Epidemiol. 2006;164:549–55.

    PubMed  Google Scholar 

  91. Shafabakhsh R, Reiter RJ, Mirzaei H, Teymoordash SN, Asemi Z. Melatonin: A new inhibitor agent for cervical cancer treatment. J Cell Physiol. 2019;234:21670–82.

    CAS  PubMed  Google Scholar 

  92. Kerenyi NA, Pandula E, Feuera G. Why the incidence of cancer is increasing: the role of ‘light pollution’. Med Hypotheses. 1990;33:75–8.

    CAS  PubMed  Google Scholar 

  93. Straif K, Baan R, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Benbrahim-Tallaa L, Cogliano V. On behalf of the WHO International Agency for Research on Cancer monograph working group, carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007;8:1065–6.

    PubMed  Google Scholar 

  94. Hill SM, Frasch T, Xiang S, Yuan L, Duplessis T, Mao L. Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther. 2009;8:337–46.

    CAS  PubMed  Google Scholar 

  95. Sanchez-Barcelo E, Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C. Melatonin-estrogen interactions in breast cancer. J Pineal Res. 2005;38:217–22.

    CAS  PubMed  Google Scholar 

  96. Shiu SY. Towards rational and evidence-based use of melatonin in prostate cancer prevention and treatment. J Pineal Res. 2007;45:1–9.

    Google Scholar 

  97. Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine. 2005;27:179–88.

    CAS  PubMed  Google Scholar 

  98. Blask DE, Sauer LA, Daunchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implication for circadian-based cancer therapy. Curr Top Med Chem. 2002;2:113–32.

    CAS  PubMed  Google Scholar 

  99. Korkmaz A, Sanchez-Barcelo EJ, Tan DX, Reiter RJ. Role of melatonin in the epigenetic regulation of breast cancer. Breast Cancer Res Treat. 2009;115:13–27.

    CAS  PubMed  Google Scholar 

  100. Leon-Blanco MM, Guerrero JM, Reiter RJ, Calvo JR, Pozo D. Melatonin inhibits telomerase activity in the MCF-7 tumor cell live both in vivo and in vitro. J Pineal Res. 2003;35:204–11.

    CAS  PubMed  Google Scholar 

  101. Girgert R, Bartsch C, Hill SM, Kreienberg R, Hauf V. Tracking the elusive antiestrogenic effect of melatonin: a new methodological approach. Neuroendocrinol Lett. 2003;24:440–4.

    CAS  PubMed  Google Scholar 

  102. Cos J, Fernandez R, Guezmes A, Sanchez-Barcelo EJ. Influcence of melatonin on invasive and metastic properties of MCF-7 human breast cancer cells. Cancer Res. 1998;58:4383–90.

    CAS  PubMed  Google Scholar 

  103. Jung-Hynes B, Reiter RJ, Ahmad N. Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res. 2010;48:9–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Alvarez-García V, González A, Alonso-González C, Martínez-Campa C, Cos S. Melatonin interferes in the desmoplastic reaction in breast cancer by regulating cytokine production. J Pineal Res. 2012;52:282–90.

    PubMed  Google Scholar 

  105. Alvarez-García V, González A, Alonso-González C, Martínez-Campa C, Cos S. Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res. 2013;54:373–80.

    PubMed  Google Scholar 

  106. Grin W, Grünberger WA. Significant correlation between melatonin deficiency and endometrial cancer. Gynecol Obstet Investig. 1998;45:62–5.

    CAS  Google Scholar 

  107. Benitez-King G, Soto-Vega E, Ramirez-Rodriguez G. Melatonin modulates microfilament phenotypes in epithelial cells: implications for adhesion and inhibition of cancer cell migration. Histol Histopathol. 2009;24:789–99.

    CAS  PubMed  Google Scholar 

  108. Alonso-González C, González A, Martínez-Campa C, Gómez-Arozamena J, Cos S. Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair. J Pineal Res. 2015;58:189–97.

    PubMed  Google Scholar 

  109. Alonso-González C, González A, Martínez-Campa C, Menendez-Menendez J, Gomez-Arozamena J, Garcia-Vidal A, Cos S. Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis. Cancer Lett. 2016;370:145–52.

    PubMed  Google Scholar 

  110. Schernhammer ES, Kroenke CH, Laden F, Hankinson SE. Night work and risk of breast cancer. Epidemiology. 2006;17:108–11.

    PubMed  Google Scholar 

  111. Menéndez-Menéndez J, Martínez-Campa C. Melatonin: an anti-tumor agent in hormone-dependent cancers, review article. Int J Endocrinol. 2018:3271948.

  112. Cohen M, Lippman M, Chabner B. Pineal gland and breast cancer. Lancet. 1978;312:P1381–2.

    Google Scholar 

  113. Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Colditz GA. Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Nat Cancer Inst. 2001;93:1563–8.

    CAS  PubMed  Google Scholar 

  114. Tamarkin L, Danforth D, Lichter A, Cohen M, Chabner B, Lippman M. Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science. 1982;216:1003–5.

    CAS  PubMed  Google Scholar 

  115. Bartsch C, Bartsch H, Karasek M. Melatonin in clinical oncology. Neuroendocrinol Lett. 2002;23:30–8.

    CAS  PubMed  Google Scholar 

  116. Molis TM, Spriggs LL, Hill SM. Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. Mol Endocrinol. 1994;8:1681–90.

    CAS  PubMed  Google Scholar 

  117. Nowfar S, Treplitzky SR, Melancon K, Kiefer TL, Chieng Q, Dwivedi PD, Bischoff ED, Moroz K, Anderson MB, Dai J, Lai N, Yuan L, Hill SM. Tumor prevention by 9-cis-retinioic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin. Breast Cancer Res Treat. 2002;72:33–43.

    CAS  PubMed  Google Scholar 

  118. Cos S, González A, Martínez-Campa C, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ. Estrogen signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev. 2006;30:118–28.

    CAS  PubMed  Google Scholar 

  119. Kubatka P, Zubor P, Busselberg D, Kwon TK, Adamek M, Petrovic D, Opatrilova R, Gazdikova K, Caprnda M, Rodrigo L, Danko J, Kruzliak P. Melatonin and breast cancer: evidences from preclinical and human studies. Crit Rev Oncology/Hematol. 2018;122:133–43.

    Google Scholar 

  120. Cos S, Alvarez-García V, González A, Alonso-González C, Martínez-Campa C. Melatonin modulation of crosstalk among malignant epithelial, endothelial and adipose cells in breast cancer (review). Oncol Lett. 2014;8:487–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. James P, Bertrand KA, Hart JE, Schernhammer ES, Tamimi RM, Laden F. Outdoor light at night and breast cancer incidence in the nurses’ health study II. Env Health Perspectives. 2017;125:087010.

    Google Scholar 

  122. Garcia-Saenz A, Sánchez de Miguel A, Espinosa A, Valentin A, Aragonés N, Llorca J, Amiano P, Sánchez VM, Guevara M, Capelo R, Tardon A, Peiró-Perez R, Jiménez-Moleón JJ, Roca-Barceló A, Pérez-Gómez B, Dierssen-Sotos T, Fernández-Villa T, Moreno-Iribas C, Moreno V, García-Pérez J, Castaño-Vinyals G, Pollán M, Aubé M, Kogevinas M. Evaluating the association between artificial light-at-night exposure and breast and prostate cancer risk in Spain (MCC-Spain study). Env Health Perspectives. 2018;126:047011.

    Google Scholar 

  123. Stevens RG, Rea MS. Light in a built environment: potential role of circadian disruption in endocrine disruption and breast cancer. Cancer Causes Control. 2001;12:279–87.

    CAS  PubMed  Google Scholar 

  124. Hansen J. Increased breast cancer risk among women who work predominantly at night. Epidemiology. 2001;12:74–7.

    CAS  PubMed  Google Scholar 

  125. Coleman MP, Reiter RJ. Breast cancer, blindness and melatonin. Eur J Cancer Clin Oncol. 1992;28:501–3.

    CAS  Google Scholar 

  126. Xiang S, Dauchy RT, Hauch A, Mao L, Yuan L, Wren MA, Belancio VP, Mondal D, Frasch P, Blask DE, Hill SM. Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal. J Pineal Res. 2015;59:60–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Regelson W, Pierpaoli MD. Melatonin: A rediscovered antitumor hormone? Its relation to surface receptors sex steroid metabolism, immunologic response, and chronobiologic factors in tumor growth and therapy. Cancer Investig. 1987;5:379–85.

    CAS  Google Scholar 

  128. Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39:360–6.

    CAS  PubMed  Google Scholar 

  129. Altun A, Ugur-Altun B. Melatonin: therapeutic and clinical utilization. Int J Clinical Practice. 2007;61:835–45.

    CAS  Google Scholar 

  130. Pawlikowsky M, Winczyk K, Karasek M. Oncostatic action of melatonin: facts and question marks. Neuroendocrinol Lett. 2002;23:24–9.

    Google Scholar 

  131. Chao YH, Wu KH, Yeh CM, Su SC, Reiter RJ, Yang SF. The potential utility of melatonin in the treatment of childhood cancer. J Cell Physiol. 2019;234:19158–66.

    CAS  PubMed  Google Scholar 

  132. Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S. Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection. J Pineal Res. 2011;50:374–80.

    CAS  PubMed  Google Scholar 

  133. Najafi M, Shayesteh MRH, Mortezaee K, Farhood B, Haghi-Aminjan H. The role of melatonin on doxorubicin-induced cardiotoxicity: a systematic review. Life Sci. 2020;241:117173.

    CAS  PubMed  Google Scholar 

  134. Imenshahidi M, Karimi G, Hosseinzadeh H. Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review. Naunyn Schmiedebergs Archives Pharmacol. 2020;393:521–36.

    CAS  Google Scholar 

  135. Zarezadeh M, Khorshidi M, Emami M, Janmohammadi P, Kord-varkaneh H. Mousavi SM, Mohammed SH, Saedisomeolia A, Alizadeh S. Melatonin supplementation and pro-inflammatory mediators: a systematic review and meta-analysis of clinical trials. Eur J Nutr 2019; https://doi.org/10.1007/s00394-019-02123-0, 59, 1803, 1813.

  136. Jang SS, Kim WD, Park WY. Melatonin exerts differential actions on X-ray radiation-induced apoptosis in normal mice splenocytes and Jurkat leukemia cells. J Pineal Res. 2009;47:147–55.

    CAS  PubMed  Google Scholar 

  137. Ishitobi M, Shiba M, Nakayama T, Motomura K, Koyama H, Nishiyama K, Tamaki Y. Treatment sequence of aromatase inhibitors and radiotherapy and long-term outcomes of breast cancer patients. Anticancer Res. 2014;34:4311–4.

    PubMed  Google Scholar 

  138. Jawed S, Kim B, Ottenhof T, Brown GM, Werstiuk ES, Niles LP. Human melatonin MT1 receptor induction by valproic acid and its effects in combination with melatonin on MCF-7 breast cancer cell proliferation. Eur J Pharmacol. 2007;560:17–22.

    CAS  PubMed  Google Scholar 

  139. Anisimov VN, Alimova IN, Baturin DA, Popovich IG, Zabezhinski MA, Manton KG, Semenchenko AV, Yashin AI. The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice. Int J Cancer. 2003;103:300–5.

    CAS  PubMed  Google Scholar 

  140. Najafi M, Salehi E, Farhood B, Nashtaei MS, Khanlarkhani N, Namjoo Z, Keywan MK. Adjuvant chemotherapy with melatonin for targeting human cancers: a review. J Cell Physiol. 2019;234(3):2356–72. https://doi.org/10.1002/jcp.27259.

    Article  CAS  PubMed  Google Scholar 

  141. Ma C, Li LX, Zhang Y, Xiang C, Ma T, Ma ZQ, Zhang ZP. Protective and sensitive effects of melatonin combined with Adriamycin on ER+ (estrogen receptor) breast cancer. Eur J Gynaecol Oncol. 2016;36:197–202.

    Google Scholar 

  142. Kosar PA, Naziroglu M, Ovey IS, Cig B. Synergic effects of doxorubicin and melatonin on apoptosis and mitochondrial oxidative stress in MCF-7 breast cancer cells: involvement of TRPV1 channels. J Membrane Biol. 2016;249:129–40.

    CAS  Google Scholar 

  143. Lissoni P, Tancini G, Barni S, Paolorossi F, Ardizzoia A, Conti A, Maestroni G. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. J Pineal Res. 1997;5:126–9.

    CAS  Google Scholar 

  144. Dubbels R, Reiter RJ, Goebel A, Schnakenberg GE, Ehlers C, Schiwara HW, Schloot W. Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res. 1995;18:28–31.

    CAS  Google Scholar 

  145. Ferrua B, Masseyeff R. Immunoassay of melatonin with enzyme-labeled antibodies. J Immunoass. 1985;6:79–94.

    CAS  Google Scholar 

  146. Honma A, Revell VL, Gunn PJ, Davies SK, Middleton B, Raynaud FI, Skene DJ. Effect of acute total sleep deprivation on plasma melatonin, cortisol and metabolite rhythms in females. Eur J Neurosci. 2020;51:366–78.

    PubMed  Google Scholar 

  147. Sengupta A, Weljie AM. Metabolism of sleep and aging: bridging the gap using metabolomics. Nutr Health Aging. 2019;5:167–84.

    CAS  Google Scholar 

  148. Xie S, Fan W, He H, Huang F. Role of melatonin in the regulation of pain. J Pain Res. 2020;13:331–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Mills MH, Finlay DC, Haddad PR. Determination of melatonin and mono-amines in rat pineal using reversed-phase ion-interaction chromatography with fluorescence detection. J Chromatogr A. 1991;564:93–102.

    CAS  Google Scholar 

  150. Peniston-Bird JF, Di WL, Street CA, Kadva A, Stalteri MA, Silman SE. HPLC assay of melatonin in plasma with fluorescence detection. Clin Chem. 1993;39:2242–7.

    CAS  PubMed  Google Scholar 

  151. Chin JR. Determination of six indolic compounds, including melatonin, in rat pineal using high-performance liquid chromatography with serial fluorimetric-electrochemical detection. J Chromatogr. 1990;528:111–21.

    CAS  PubMed  Google Scholar 

  152. Vieira R, Míguez J, Lerna M, Aldegunde M. Pineal and plasma melatonin a determined by high-performance liquid chromatography with electrochemical detection. Anal Biochem. 1992;205:300–5.

    CAS  PubMed  Google Scholar 

  153. Skene DJ, Leone RM, Young IM, Silman RE. The assessment of a plasma melatonin assay using gas chromatography negative ion chemical ionization mass spectrometry. Biomed Mass Spectrom. 1983;10:655–9.

    CAS  PubMed  Google Scholar 

  154. Fourtillan JB, Gobin P, Faye B, Girault J. A highly sensitive assay of melatonin at the femotogram level in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry. Biol Mass Spectrom. 1994;23:499–509.

    CAS  PubMed  Google Scholar 

  155. Simonin G, Bru L, Lelièvre E, Jeanniot J-P, Bromet N, Walther B, Boursier-Neyret C. Determination of melatonin in biological fluids in the presence of the melatonin agonist S 20098: comparison of immunological techniques and GC-MS methods. J Pharm Biomed Anal. 1999;21:591–601.

    CAS  PubMed  Google Scholar 

  156. Yang S, Zheng X, Xu Y, Zhou X. Rapid determination of serum melatonin by ESI–MS–MS with direct sample injection. J Pharm Biomed Anal. 2002;30:781–90.

    CAS  PubMed  Google Scholar 

  157. Jensen MA, Hansen AM, Abrahamsson P, Norgaard AW. Development and evaluation of a liquid chromatography tandem mass spectrometry method for simultaneous determination of salivary melatonin, cortisol and testosterone. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879:2527–32.

    CAS  PubMed  Google Scholar 

  158. Carter MD, Calcutt MW, Malow BA, Rose KL, Hachey DL. Quantitation of melatonin and N-acetylserotonin in human plasma by nanoflow LC-MS/MS and electrospray LC-MS/MS. J Mass Spectrom. 2012;47:277–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Khan SA, George R, Charles BG, Taylor P, Heussler HS, Couper DM, McGuire TM, Pache D, Norris D. Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry. Ther Drug Monit. 2013;35:388–95.

    CAS  PubMed  Google Scholar 

  160. Wang H, Walaszczyk EJ, Li K, Chung-Davidson Y-W, Li W. High-performance liquid chromatography with fluorescence detection and ultra-performance liquid chromatography with electrospray tandem mass spectrometry method for the determination of indoleamine neurotransmitters and their metabolites in sea lamprey plasma. Anal Chim Acta. 2012;721:147–53.

    CAS  PubMed  Google Scholar 

  161. Hadrevi J, Jonsdottir IH, Jansson P-A, Eriksson JW, Sjörs A. Plasma metabolomic patterns in patients with exhaustion disorder. Stress. 2019;22:17–26.

    CAS  PubMed  Google Scholar 

  162. Diallo I, Pak VM. Metabolomics, sleepiness and sleep duration in sleep apnea. Sleep and Breath. 2020; https://doi.org/10.1007/s11325-019-01969-2.

  163. Härtter S, Morita S, Bodin K, Ursing C, Tybring C, Bertilsson L. Determination of exogenous melatonin and its 6-hydroxy metabolite in human plasma by liquid chromatography–mass spectrometry. Ther Drug Monit. 2001;23:282–6.

    PubMed  Google Scholar 

  164. Xu J, Huang L. Urinary 6-sulfatoxymelatonin level and breast cancer risk: systematic review and meta-analysis. Sci Rep. 2017;7:5353–63.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The logistic, administrative and technical support offered by the Research Center for Applied Biotechnology in Diagnosis and Molecular Therapy (BIODIATECH) Cluj-Napoca is acknowledged.

Funding

This research received no external funding.

Author information

Author notes

  1. Andreea Iulia Socaciu, Răzvan Ionuţ, and Mihai Adrian Socaciu contributed equally to this work.

Authors and Affiliations

  1. Department of Occupational Health, University of Medicine and Pharmacy “Iuliu Haţieganu”, Cluj-Napoca, Romania

    Andreea Iulia Socaciu, Răzvan Ionuţ, Andreea Petra Ungur, Maria Bârsan & Armand Gabriel Râjnoveanu

  2. Department of Medical Imaging, University of Medicine and Pharmacy “Iuliu Haţieganu”, Cluj-Napoca, Romania

    Mihai Adrian Socaciu

  3. Department of Radiology, University of Medicine and Pharmacy “Iuliu Haţieganu”, Cluj-Napoca, Romania

    Angelica Chiorean

  4. Department of Biochemistry, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania

    Carmen Socaciu

Authors
  1. Andreea Iulia Socaciu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Răzvan Ionuţ
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mihai Adrian Socaciu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreea Petra Ungur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Bârsan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angelica Chiorean
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carmen Socaciu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Armand Gabriel Râjnoveanu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carmen Socaciu.

Ethics declarations

Conflict of interest

Not applicable. The authors declare that there is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Socaciu, A.I., Ionuţ, R., Socaciu, M.A. et al. Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases. Rev Endocr Metab Disord 21, 465–478 (2020). https://doi.org/10.1007/s11154-020-09570-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-020-09570-9

Keywords

Search

Navigation