Melatonin in Human Cancer: Therapeutic Possibilities



The recent discovery in the neuropsychoimmunology of tumors has demonstrated that human body may produce not only pro-tumoral hormones such as estrogens, androgens, and perhaps GH itself but also antitumor endocrine molecules, the most important of them represented by pineal hormones, melatonin as the most investigated of them. The antitumor activity of melatonin has been demonstrated by a great number of experimental studies, and it has been proven to be able to exert the overall potential antitumor mechanisms, commonly used by the conventional clinical oncology, including (1) antiproliferative cytotoxic action, mainly on melatonin receptor-expressing tumor cells; (2) inhibition of growth factor receptor activation; (3) inhibitory effect on tumor angiogenesis; (4) inhibition of tumor growth factor secretion; and (5) stimulation of the antitumor immunity, namely, by stimulating IL-2 secretion by T helper lymphocytes and IL-12 production by dendritic cells. In addition, melatonin could reserve interesting therapeutic results in the palliative therapy of cancer, particularly by counteracting the onset of the neoplastic cachexia by inhibiting the TNF-alpha secretion. Unfortunately, despite the great number of the experimental evidences, very few clinical studies with melatonin have been carried up to now in the treatment of human neoplasms, at least from a palliative point of view, to improve the quality of life.


Melatonin Cytokines Growth factors Antitumor immunity Apoptosis 


  1. 1.
    Foon KA. Biological response modifiers: the new immunotherapy. Cancer Res. 1989;49:1621–7.PubMedGoogle Scholar
  2. 2.
    Rubinow DR. Brain, behaviour and immunity: an interactive system. J Natl Cancer Inst Monogr. 1994;10:79–82.Google Scholar
  3. 3.
    Maestroni GJM. The immunoneuroendocrine role of melatonin. J Pineal Res. 1993;14:1–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Plotnikoff NP, Miller GC. Enkephalins as immunomodulators. Int J Immunopharmacol. 1983;5:437–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Grotenhermen F. Pharmacology of cannabinoids. Neuro Endocrinol Lett. 2004;25:14–22.PubMedGoogle Scholar
  6. 6.
    Roberts AB, Sporn AB. Growth factors and transformation. Cancer Surv. 1986;5:405–11.PubMedGoogle Scholar
  7. 7.
    Welsch C, Nagasawa H. Prolactin and murine tumorigenesis: a review. Cancer Res. 1977;37:951–63.PubMedGoogle Scholar
  8. 8.
    Ben-Shlomo A, Melmed S. Growth hormone excess and cancer. J Antiag Med. 2001;4:301–9.Google Scholar
  9. 9.
    Benlot C, Lévy L, Fontanaud P, Roche A, Rouannet P, Joubert D. Somatostatin and growth hormone-releasing hormone in normal and tumoral breast tissue: endogenous content, in vitro pulsatile release, and regulation. J Clin Endocrinol Metab. 1997;82:690–6.PubMedGoogle Scholar
  10. 10.
    Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.PubMedCrossRefGoogle Scholar
  11. 11.
    Buswell RS. The pineal and neoplasia. Lancet. 1975;1:34–5.PubMedCrossRefGoogle Scholar
  12. 12.
    El-Domeiri AAH, Das Gupta TK. Reversal by melatonin of the effect of pinealectomy on tumor growth. Cancer Res. 1973;33:2830–3.PubMedGoogle Scholar
  13. 13.
    Sze SF, Ng TB, Liu WK. Antiproliferative effect of pineal indoles on cultured tumor cell lines. J Pineal Res. 1993;14:27–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Tsuchiya H, Shimizu H, Inuma M. Beta-carboline alkaloids in crude drugs. Chem Pharm Bull. 1999;47:440–3.CrossRefGoogle Scholar
  15. 15.
    Anisomov VN, Arutjunyan V, Khavinson VK. Effects of pineal peptide preparation epithalamin on free-radical processes in humans and animals. Neuro Endocrinol Lett. 2001;22:9–18.Google Scholar
  16. 16.
    Lapin V. Pineal gland and malignancy. Oster Z Onkol. 1976;3:51–60.Google Scholar
  17. 17.
    Bartsch C, Bartsch H, Lippert TH. The pineal gland and cancer: facts, hypotheses and perspectives. Cancer J. 1992;5:194–9.Google Scholar
  18. 18.
    Maestroni JGM, Conti A, Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci. 1988;521:140–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Mazzocchi G, Carughi S, De Cata A, La Viola M, Vendemmiale G. Melatonin and cortisol serum levels in lung cancer patients at different stages of disease. Med Sci Monit. 2005;11:284–8.Google Scholar
  20. 20.
    Hajdu SI, Porro RS, Lieberman PH, Foote Jr FW. Degeneration of the pineal gland of patients with cancer. Cancer. 1972;29:706–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Huang Y, Chang Y, Wang X, Jiang J, Frank SJ. Growth hormone alters epidermal growth factor receptor binding affinity via activation of extracellular signal-regulated kinases in 3T3-F442A cells. Endocrinology. 2004;145:3297–306.PubMedCrossRefGoogle Scholar
  22. 22.
    Siejka A, Awinicka H, Komorowski J, Schally AV, Stpie T, Krupi R, Stpie H. GH-RH antagonist (MZ-4-71) inhibits VEGF secretion and proliferation of murine endothelial cells. Life Sci. 2003;72:2473–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Taverna D, Groner B, Hynes NE. Epidermal growth factor receptor, platelet-derived growth factor receptor and c-erb B-2 receptor activation all promote growth but have distinctive effects upon mouse mammary epithelial cell differentiation. Cell Growth Differ. 1991;2:145–54.PubMedGoogle Scholar
  24. 24.
    Zou W. Regulatory T, cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.PubMedCrossRefGoogle Scholar
  25. 25.
    Battelli E, Oukka M, Kuchroo VK. TH-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.CrossRefGoogle Scholar
  26. 26.
    Gabrilovich DL, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumor inhibits the functional maturation of dendritic cells. Nat Med. 1996;2:1096–103.PubMedCrossRefGoogle Scholar
  27. 27.
    Reiss M. TGF-beta and cancer. Microbes Infect. 1999;1:1327–47.PubMedCrossRefGoogle Scholar
  28. 28.
    Kim R, Emi M, Tanabe K, Uchida Y, Toge T. The role of Fas ligand and transforming growth factor-beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential target for cancer therapy. Cancer. 2004;100:2281–91.PubMedCrossRefGoogle Scholar
  29. 29.
    Lerma E, Romero M, Callardo A, Pons C, Munoz J, Fuentes J, Llovera B, Catasus L, Prati J. Prognostic significance of the Fas receptor/Fas-ligand system in cervical squamous cell carcinoma. Virchows Arch. 2008;452:65–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Danielczyk K, Dzjegiel P. MT 1 melatonin receptors and their role in the oncostatic action of melatonin. Postepy Hig Med Dosw. 2009;63:425–34.Google Scholar
  31. 31.
    Winczyk K, Fuss-Chmielewska K, Lawnika H, Pawlilkowski M, Karasek M. Luzindol but not 4P-PDOT diminishes the inhibitory effect of melatonin on murine colon cancer growth in vitro. Neuro Endocrinol Lett. 2009;30:657–62.PubMedGoogle Scholar
  32. 32.
    Named C, Humpeler S, Kallay E, Msteri I, Sloboda M, Rogelsperger O, Klammert N, Thalhammer T, Ekmekaoglu C. Decreased expression of the melatonin receptor 1 in human colorectal carcinomas. J Biol Regul Homeost Agents. 2011;25:531–42.Google Scholar
  33. 33.
    Hill SM, Erasch T, Xiang S, Yuan L, Duplessis T, Mao L. Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther. 2009;8:337–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin. A multitasking molecule. Prog Brain Res. 2010;181:127–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Cos S, Fernandez R. Melatonin effects on intercellular junctional communication in MCF-7 human breast cancer cells. J Pineal Res. 2000;29:166–71.PubMedCrossRefGoogle Scholar
  36. 36.
    Trosko JE, Ruch RJ. Cell-cell communication in carcinogenesis. Front Biosci. 2004;3:1171–86.Google Scholar
  37. 37.
    Lissoni P, Messina G, Brivio F, Fumagalli L, Vigoré L, Rovelli F, Maruelli L, Miceli M, Marchiori P, Porro G, Held M, Di Fede G, Uchiyamada T. Modulation of the anticancer immunity by natural agents: inhibition of T regulatory lymphocyte generation by arabinoxylan in patients with locally limited or metastatic solid tumors. Cancer Ther. 2008;6:1007–12.Google Scholar
  38. 38.
    Casado-Apico S, Martin V, Garcia-Santos G, Rodriguez-Bianco J, Sanchez-Sanchez AM, Luno E, Suarez G, Garcia-Pedrera JM, Menendez ST, Antolin I, Rodriguez C. Regulation of the expression of death receptors and their ligands by melatonin in haematological cancer cell lines and in leukaemia cell from patients. J Pineal Res. 2011;50:345–55.CrossRefGoogle Scholar
  39. 39.
    Hagimoto N, Kuwand K, Inashima I, Yashimi M, Nakamura N, Fujita M, Moeyama T, Hara N. TGF-beta-1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol. 2002;168:6470–8.PubMedGoogle Scholar
  40. 40.
    Liu F, Ng TB, Fung ML. Pineal indoles stimulate the gene expression of immunomodulating cytokines. J Neural Transm. 2001;108:397–405.PubMedCrossRefGoogle Scholar
  41. 41.
    Park SY, Yang WJ, Yi EY, Jang JY, Jung Y, Leong JW, Kim YJ. Melatonin suppresses tumor angiogenesis by inhibiting HIF- 1 alpha stabilization under hypoxia. J Pineal Res. 2010;48:178–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer. 2000;10:110–6.CrossRefGoogle Scholar
  43. 43.
    Kong X, Wang X, Xu W, Behera S, Hellermann G, Kumar A, Lockey RF, Mohapatra S, Mohapatra SS. Natriuretic peptide receptor as a novel anticancer target. Cancer Res. 2008;68:249–56.PubMedCrossRefGoogle Scholar
  44. 44.
    Lissoni P, Pittalis S, Vigoré L, Rovelli F, Vezzo R, Bramati S, Menin E, Rescaldani R, Fondrini G, Pelizzoni F, Grugni G, Morabito F. The heart as an immunomodulator organ: in vitro immune effects of the cardiac hormone atrial natriuretic peptide-alpha and their possible relevance in cardiac failure and aging. Cardiol Eld. 1993;1:227–31.Google Scholar
  45. 45.
    Bartsch H, Bartsch C. Effect of melatonin on experimental tumors under different photoperiods and times of administration. J Neural Transm. 1981;52:269–79.PubMedCrossRefGoogle Scholar
  46. 46.
    Lissoni P, Tisi E, Brivio F, Ardizzoia A, Crispino S, Barni S, Tancini G, Conti A, Maestroni GJM. Modulation of interleukin-2-induced macrophage activation in cancer patients by the pineal hormone melatonin. J Biol Regul Homeost Agents. 1991;5:154–6.PubMedGoogle Scholar
  47. 47.
    Starr KW. Growth and new growth: environmental carcinogens in the process of human ontogeny. Prog Clin Cancer. 1970;4:1–13.PubMedGoogle Scholar
  48. 48.
    Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F. Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer. 1989;25:789–95.CrossRefGoogle Scholar
  49. 49.
    Gonzales R, Sanchez A, Ferguson JA, Palmer C, Daniel C, Cohn A, Robinson WA. Melatonin therapy of advanced human malignant melanoma. Melanoma Res. 1991;1:237–43.CrossRefGoogle Scholar
  50. 50.
    Millis E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systemic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39:360–6.CrossRefGoogle Scholar
  51. 51.
    Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamps RD, Coffey RJ. Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21 via F1/CIP1 via c/EBP-beta. Nat Med. 1997;3:1233–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Conti A, Maestroni GJM. The clinical neuroimmunotherapeutic role of melatonin in oncology. J Pineal Res. 1995;19:103–10.PubMedCrossRefGoogle Scholar
  53. 53.
    Lissoni P, Paolorossi F, Ardizzoia A, Barni S, Chilelli M, Tancini G, Conti A, Maestroni GJM. 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 poor clinical state. J Pineal Res. 1997;23:15–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. Eur J Cancer. 1999;35:1688–92.PubMedCrossRefGoogle Scholar
  55. 55.
    Lissoni P, Barni S, Tancini G, Ardizzoia A, Ricci G, Aldeghi R, Brivio F, Tisi E, Rovelli F, Rescaldani R, Quadro G, Maestroni GJM. A randomised study with subcutaneous low-dose interleukin-2 alone vs interleukin-2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer. 1994;69:196–9.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Siu SW, Lau TK, Tam PC, Shiu SY. Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate. 2002;52:106–22.PubMedCrossRefGoogle Scholar
  57. 57.
    Lissoni P, Ardizzoia A, Barni S, Paolorossi F, Tancini G, Meregalli S, Esposti D, Zubelewicz B, Braczowski R. A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast cancer patients. Oncol Rep. 1995;2:871–3.PubMedGoogle Scholar
  58. 58.
    Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni GJM. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer. 1994;73:699–701.PubMedCrossRefGoogle Scholar
  59. 59.
    Lissoni P, Meregalli S, Nasetto L, Barni S, Tancini G, Fossati V, Maestroni G. Increased survival time in brain glioblastoma by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996;53:43–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Lewis JW, Shavit Y, Terman GW. Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth. Peptides. 1983;4:635–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F. Biotherapy with the pineal immunomodulating hormone melatonin plus Aloe vera in untreatable advanced solid neoplasms. Nat Immun. 1998;16:27–33.PubMedCrossRefGoogle Scholar
  62. 62.
    Shishodia S, Harikumar KB, Dass S, Ramawat KG, Aggarwal BB. The guggul for chronic diseases: ancient medicine, modern targets. Anticancer Res. 2008;28:3647–64.PubMedGoogle Scholar
  63. 63.
    Somparn P, Phisalaphong C, Nakornchal S, Unchern S, Morales NP. Comparative antioxidant activities of curcumin and its demethoxy and hydrogenated derivatives. Biol Pharm Bull. 2007;30:74–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Viviani S, Negretti E, Orazi A, Sozzi G, Santoro A, Lissoni P, Esposti G, Fraschini F. Preliminary studies on melatonin in the treatment of myelodysplastic syndromes following cancer chemotherapy. J Pineal Res. 1990;8:347–51.PubMedCrossRefGoogle Scholar
  65. 65.
    Lissoni P, Mandalà M, Rossini F, Fumagalli L, Barni S. Thrombopoietic property of the pineal hormone melatonin. Hematology. 1999;4:335–43.PubMedGoogle Scholar
  66. 66.
    Lissoni P, Mandalà M, Brivio F. Abrogation of the negative influence of opioids on IL-2 immunotherapy of renal cell cancer by melatonin. Eur Urol. 2000;38:115–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Lissoni P, Brivio O, Brivio F, Barni S, Tancini G, Crippa D, Meregalli S. Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. J Pineal Res. 1996;21:239–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  1. 1.Department of Medical OncologyAzienda Ospedaliera San GerardoMonzaItaly

Personalised recommendations