Abstract
Melatonin has been reported to be involved in the feedback between neuroendocrine and immune functions and to exert oncostatic actions. Likewise, this hormone seems to lengthen life span in healthy animals. As of present, most studies have analysed the therapeutic effect of melatonin on cancer growth, but few have tested the preventive effect of melatonin in reducing the risk of cancer. Thus, the aim of this study was to evaluate the preventive-therapeutic effects of melatonin on rats with DMBA-induced mammary tumours, and to examine the effect of melatonin on the first line of cell defence against cancer (macrophages and NK cells) and on some of the neuroendocrine factors that are involved in the development of tumours (prolactin and catecholamines). Melatonin treatment (5 mg/day/animal) began one month prior to DMBA (9,10-dimethyl-1,2-benzanthracene) administration to females Sprague Dawley rats. It was found that the treatment led to an increase in survival and in latency time in the tumour-bearing rats. Although the melatonin treatment did not influence either the phagocytic capacity of macrophages or the number of peripheral blood NK cells, it did stabilise the levels of prolactin by returning the concentrations of this hormone to those of the healthy animals. We conclude that melatonin can exert an oncostatic action, lengthening the survival time of mammary tumour-bearing animals, and suggest that this effect is due, at least in part, to regulating the neuroendocrine parameters of tumour-bearing animals, bringing them closer to their optimal physiological status. (Mol Cell Biochem 268: 25–31, 2005)
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Russo IH, Russo J: Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect 104: 938–967, 1996
Bartsch C, Bartsch H: Melatonin in cancer patients and in tumor-bearing animals. Adv Exp Med Biol 467: 247–264, 1999
Blask DE, Sauer LA, Dauchy RT: Melatonin as a chronobiotic/ anticancer agent: Cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2: 113–132, 2002
Lissoni P, Malugani F, Malysheva O, Kozlov V, Laudon M, Conti A, Maestroni G: Neuroimmunotherapy of untreatable metastatic solid tumours with subcutaneous low-dose interleukin-2, melatonin and naltrexone: Modulation of interleukin-2-induced antitumour immunity by blocking the opioid system. Neuroendocrinol Lett 23: 341–344, 2002
Mediavilla MD, San Martin M, Sanchez-Barcelo EJ: Melatonin inhibits mammary gland development in female mice. J Pineal Res 13: 13–19, 1992
Currier NL, Sun LZ, Miller SC: Exogenous melatonin: Quantitative enhancement in vivo of cells mediating non-specific immunity. J Neuroimmunol 104: 101–108, 2000
Pioli C, Caroleo MC, Nistico G, Doria G: Melatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferation. Int J Immunopharmacol 15: 463–468, 1993
Mhatre MC, Shah PN, Juneja HS: Effect of varying photoperiods on mammary morphology, DNA synthesis, and hormone profile in female rats. J Natl Cancer Inst 72: 1411–1416, 1984
Sanchez-Barcelo EJ, Mediavilla MD, Tucker HA: Influence of melatonin on mammary gland growth: In vivo and in vitro studies. Proc Soc Exp Biol Med 194: 103–107, 1990
Subramanian A, Kothari L: Melatonin, a suppressor of spontaneous murine mammary tumours. J Pineal Res 10: 136–140, 1991
Thyagarajan S, Madden KS, Stevens SY, Felten DL: Anti-tumour effect of L-deprenyl is associated with enhanced central and peripheral neurotransmission and immune reactivity in rats with carcinogen-induced mammary tumours. J Neuroimmunol 109: 95–104, 2000
Blask DE, Pelletier DB, Hill SM, Lemus-Wilson A, Grosso DS, Wilson ST, Wise ME: Pineal melatonin inhibition of tumour promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: Potential involvement of antiestrogenic mechanisms in vivo. J Cancer Res Clin Oncol 117: 526–532, 1991
Siegrist C, Benedetti C, Orlando A, BeltraN JM, Tuchscherr L, Noseda CM, Brusco LI, Cardinali DP: Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. J Pineal Res 30: 34–42, 2001
Loscher W, Mevissen M, Haussler B: Seasonal influence on 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis in Sprague-Dawley rats under controlled laboratory conditions. Pharmacol Toxicol 81: 265–270, 1997
Aoyama H, Mori N, Mori W: Anti-glucocorticoid effects of melatonin on adult rats. Acta Pathol Jpn 37: 1143–1148, 1987
Kubatka P, Bojkova B, M Cikova-Kalicka K, Mnichova-Chamilova M, Adamekova E, Ahlers I, Ahlersova E, Cermakova M: Effects of tamoxifen and melatonin on mammary gland cancer induced by N-methyl-N-nitrosourea and by 7,12-dimethylbenz(a)anthracene, respectively, in female Sprague-Dawley rats. Folia Biol (Praha) 47: 5–10, 2001
Ortega E, Garcia JJ, Saez MC, De La Fuente M: Changes with aging in the modulation of macrophages by norepinephrine. Mech Ageing Dev 118: 103–114, 2000
Pinilla L, Gonzalez LC, Tena-Sempere M, Aguilar E: Interactions between serotoninergic and aminoacidergic pathways in the control of PRL secretion in prepubertal male rats. J Physiol Biochem 57: 237–244, 2001
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958
Cos S, Garijo F, Corral J, Mediavilla MD, Sanchez-Barcelo EJ: Histopathologic features of DMBA-induced mammary tumours in blind-underfed, blind-anosmic, and blind cold-exposed rats: Influence of the pineal gland. J Pineal Res 6: 221–231, 1989
Anisimov NV: The role of pineal gland in breast cancer development. Crit Rev Oncol Hematol 46: 221–234, 2003
Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S: Melatonin: Reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmaco l54: 1299–1321, 2002
Maestroni GJ, Covacci V, Conti A: Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumour-bearing mice. Cancer Res 54: 2429–2432, 1994
Morrey KM, Mclachlan JA, Serkin CD, Bakouche O: Activation of human monocytes by the pineal hormone melatonin. J Immunol 153: 2671–2680, 1994
Skene DJ, Bojkowski CJ, Currie JE, Wright J, Boulter PS, Arendt J: 6-sulphatoxymelatonin production in breast cancer patients. J Pineal Res 8: 269–276, 1990
Sanchez-Barcelo EJ, Cos S, Mediavilla MD: Influence of pineal gland function on the initiation and growth of hormone-dependent breast tumours. Possible mechanisms. In: D. Gupta, A. Attanasio, R.J. Reiter, (eds). The Pineal Gland and Cancer, Brain Research Promotion, Tübingen, 1988, pp 221–232
Mockova K, Mnichova M, Kubatka P, Bojkova B, Ahlers I, Ahlersova E: Mammary carcinogenesis induced in Wistar:han rats by the combination of ionizing radiation and dimethylbenz(a)anthracene: Prevention with melatonin. Neoplasma 47: 227–229, 2000
Brzezinski A: Melatonin in humans. N Engl J Med 336: 186–195, 1997
Garcia-Perganeda A, Guerrero JM, Rafii-EL-Idrissi M, Paz Romero M, Pozo D, Calvo JR: Characterization of membrane melatonin receptor in mouse peritoneal macrophages: Inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein. J Neuroimmunol 95: 85–94, 1999
Toujas L, Delcros JG, Diez E, Gervois N, Semana G, Corradin G, Jotereau F: Human monocyte-derived macrophages and dendritic cells are comparably effective in vitro in presenting HLA class I-restricted exogenous peptides. Immunology 91: 635–642, 1997
Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF: Evidence for a direct action of melatonin on the immune system. Biol Signals 3: 107–117, 1994
Kishi A, Takamori Y, Ogawa K, Takano S, Tomita S, Tanigawa M, Niman M, Kishida T, Fujita S: Differential expression of granulysin and perforin by NK cells in cancer patients and correlation of impaired granulysin expression with progression of cancer. Cancer Immunol Immunother 50: 604–614, 2002
Nannmark U, Basse P, Johansson BR, Kuppen P, Kjergaard J, Hokland M: Morphological studies of effector cell-microvessel interactions in adoptive immunotherapy in tumour-bearing animals. Nat Immun 15: 78–86, 1996–97
Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Brenton Huggins. Cancer Res 45: 3415–3443, 1985
Meites J: Relation of the neuroendocrine system to the development and growth of experimental mammary tumours. J Neural Transm 48: 25–42, 1980
Harada Y: Pituitary role in the growth of metastasizing MRMT-1 mammary carcinoma in rats. Cancer Res 36: 18–22, 1976
Takahashi M, Iizuka S, Watanabe T, Midori Y, Ando J, Wakabayashi K, Maekawa A: Possible mechanisms underlying mammary carcinogenesis in female Wistar rats by nitrofurazone. Cancer Lett 156: 177–184, 2000
Pasqualini C, Bojda F, Kerdelhue B: In vitro estrogen-like effects of 7,12-dimethylbenz(a)anthracene on anterior pituitary dopamine receptors of rats. Cancer Res 48: 6434–6437, 1988
Pasqualini C, Sarrieau A, Dussaillant M, Corbani M, Bojda-Diolez F, Rostene W, Kerdelhue B: Estrogen-like effects of 7,12-dimethylbenz(a)anthracene on the female rat hypothalamo-pituitary axis. J Steroid Biochem 36: 485–491, 1990
Patel DD, Bhatavdekar JM, Chikhlikar PR, Ghosh N, Suthar TP, Shah NG, Mehta RH, Balar DB: Node negative breast carcinoma: Hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators. J Surg Oncol 62: 86–92, 1996
Strungs I, Gray RA, Rigby HB, Strutton G: Two case reports of breast carcinoma associated with prolactinoma. Pathology 29: 320–323, 1997.
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Saez, M.C., Barriga, C., Garcia, J.J. et al. Effect of the preventive-therapeutic administration of melatonin on mammary tumour-bearing animals. Mol Cell Biochem 268, 25–31 (2005). https://doi.org/10.1007/s11010-005-2994-3
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DOI: https://doi.org/10.1007/s11010-005-2994-3