Molecular and Cellular Biochemistry

, Volume 278, Issue 1–2, pp 15–20 | Cite as

Melatonin increases the survival time of animals with untreated mammary tumours: Neuroendocrine stabilization

  • M. C. Saez
  • C. Barriga
  • J. J. Garcia
  • A. B. Rodriguez
  • J. Masot
  • E. Duran
  • E. Ortega
Article

Abstract

The aim of this study was to evaluate the therapeutic effect of melatonin, the main hormone of the pineal gland, on rats with advanced and untreated mammary tumours. Mammary tumours were chemically induced in Sprague–Dawley rats with the carcinogen 9,10-dimethyl-1,2-bezanthracene (DMBA). After the appearance of tumours the effect of melatonin (5 mg/ml per rat per day) was then evaluated on the survival time, tumour multiplicity, and tumour volume until the death of the animals. In addition, the variations in prolactin, noradrenaline and adrenaline concentrations, and in the percentage of NK cells were evaluated after one month of the treatment with melatonin. Daily administration of melatonin increased significantly the survival time of tumour-bearing animals (p<0.05 with respect to the control non-melatonin-receiving rats). The increased survival time did not correlate, however, with changes in either tumour multiplicity or tumour growth rate. Animals with mammary tumours exhibited an increase (p<0.05 with respect to healthy animals) in prolactin and catecholamine concentrations. The administration of melatonin stabilized the hormone levels, returning them to those in the basal-healthy animals. Rats with mammary tumours also presented lower percentages of NK cells, which were not increased by the administration of melatonin. The results strongly suggest that melatonin per se is beneficial during advanced breast cancer. It increases survival time, maybe by improving the homeostatic and neuroendocrine equilibrium which is imbalanced during advanced breast cancer. (Mol Cell Biochem 278: 15–20, 2005)

Key Word

DMBA mammary tumours melatonin rats 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Cohen M, Lipman M, Chabner B: Role of the pineal gland in the aetiology and treatment of breast cancer. Lancet 2: 814–816, 1978CrossRefPubMedGoogle Scholar
  2. 2.
    Tamarkin L, Danforth DN, Lichter A, DeMoss E, Cohen M, Chabner B, Lippman M: Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science 216: 1003–1005, 1982PubMedGoogle Scholar
  3. 3.
    Anisimov VN: The role of pineal gland in breast cancer development. Crit Rev Oncol Hematol 46: 221–234, 2003PubMedGoogle Scholar
  4. 4.
    Lissoni P, Paolorossi F, Tancini G, Ardizzoia A, Barni S, Brivio F, Maestroni GJ, Chilelli M: A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 74: 1466–1468, 1996PubMedGoogle Scholar
  5. 5.
    Lissoni P: Is there a role for melatonin in supportive care? Support Care Cancer 10: 110–116, 2002CrossRefPubMedGoogle Scholar
  6. 6.
    Reiter RJ, Melchiorri D, Sewerynek E, Poeggeler B, Barlow-Walden L, Chuang J, Ortiz GG, Acuna-Castroviejo D: A review of the evidence supporting melatonin’s role as an antioxidant. J Pineal Res 18: 1–11, 1995PubMedGoogle Scholar
  7. 7.
    Barriga C, Martin MI, Tabla R, Ortega E, Rodríguez AB: Circadian rhythm of melatonin, corticosterone and phagocytosis: Effect of stress. J Pineal Res 30: 180–187, 2001CrossRefPubMedGoogle Scholar
  8. 8.
    Currier NL, Sun LZ, Miller SC: Exogenous melatonin: Quantitative enhancement in vivo of cells mediating non-specific immunity. J Neuroimmunol 104: 101–108, 2000CrossRefPubMedGoogle Scholar
  9. 9.
    Blask DE, Pelletier DB, Hill SM, Lemus-Wilson A, Grosso DS, Wilson ST, Wise ME: Pineal melatonin inhibition of tumor 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, 1991CrossRefPubMedGoogle Scholar
  10. 10.
    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, 1997PubMedGoogle Scholar
  11. 11.
    Kubatka P, Bojkova BM, 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, 2001Google Scholar
  12. 12.
    Aoyama H, Mori N, Mori W: Anti-glucocorticoid effects of melatonin on adult rats. Acta Pathol Jpn 37: 1143–1148, 1987PubMedGoogle Scholar
  13. 13.
    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, 2001PubMedGoogle Scholar
  14. 14.
    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958Google Scholar
  15. 15.
    Russo J, Russo IH: Atlas and histologic classification of tumors of the rat mammary gland. J Mammary Gland Biol Neoplasia 5: 187–200, 2000CrossRefPubMedGoogle Scholar
  16. 16.
    De Jonage-Canonico MB, Lenoir V, Martin A, Scholler R, Kerdelhue B: Long term inhibition by estradiol or progesterone of melatonin secretion after administration of a mammary carcinogen, the dimethyl benz(a)anthracene, in Sprague-Dawley female rat; inhibitory effect of Melatonin on mammary carcinogenesis. Breast Cancer Res Treat 79: 365–377, 2003CrossRefPubMedGoogle Scholar
  17. 17.
    Saez MC, Barriga C, Garcia JJ, Rodríguez AB, Ortega E: Effect of the preventive-therapeutic administration of melatonin on mammary tumor-bearing animals. Mol Cell Biochem 268: 25–31, 2005CrossRefPubMedGoogle Scholar
  18. 18.
    Nandi S, Guzman RC, Yang J: Hormones and mammary carcinogenesis in mice, rats, and humans: A unifying hypothesis. Proc Natl Acad Sci USA 92: 3650–3657, 1995PubMedGoogle Scholar
  19. 19.
    Currier NL, Miller SC: Echinacea purpurea and melatonin augment natural-killer cells in leukemic mice and prolong life span. J Altern Complement Med 7: 241–251, 2001CrossRefPubMedGoogle Scholar
  20. 20.
    Karasek M, Kuzdak K, Cywinski J, Zylinska K, Smialowska A, Pluzanska A: Effect of melatonin administration in advanced breast cancer patients – preliminary report. Neuroendocrinol Lett 19: 15–19, 1998Google Scholar
  21. 21.
    Mcikova-Kalicka K, Bojkova B, Adamekova E, Mnichova-Chamilova M, Kubatka P, Ahlersova E, Ahlers I: Preventive effect of indomethacin and melatonin on 7,12-dimethybenz/a/anthracene-induced mammary carcinogenesis in female Sprague-Dawley rats. A preliminary report. Folia Biol (Praha) 47: 75–79, 2001Google Scholar
  22. 22.
    Ahlersova E, Ahlers I, Kubatka P, Bojkova B, Mocikova K, Gajdosova S, Onderkova HM: Melatonin and retinyl acetate as chemopreventives in DMBA-induced mammary carcinogenesis in female Sprague-Dawley rats. Folia Biol (Praha) 46: 69–72, 2000Google Scholar
  23. 23.
    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, 1985PubMedGoogle Scholar
  24. 24.
    Vonderhaar BK: Prolactin involvement in breast cancer. Endocr Relat Cancer 6: 389–404, 1999CrossRefPubMedGoogle Scholar
  25. 25.
    Cheung SY, Yuen MT, Choi HL, Cheng HK, Huang Y, Chen S, Chan FL: An expression study of hormone receptors in spontaneously developed, carcinogen-induced and hormone-induced mammary tumors in female Noble rats. Int J Oncol 22: 1383–1395, 2003PubMedGoogle Scholar
  26. 26.
    Vazquez SM, Pignataro O, Luthy IA: Alpha2-adrenergic effect on human breast cancer MCF-7 cells. Breast Cancer Res Treat 55: 41–49, 1999CrossRefPubMedGoogle Scholar
  27. 27.
    Drell TL 4th, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F: Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat 80: 63–70, 2003CrossRefPubMedGoogle Scholar
  28. 28.
    Bartsch C, Bartsch H, Buchberger A, Stieglitz A, Effenberger-Klein A, Kruse-Jarres JD, Besenthal I, Rokos H, Mecke D: Serial transplants of DMBA-induced mammary tumors in Fischer rats as a model system for human breast cancer. VI. The role of different forms of tumor-associated stress for the regulation of pineal melatonin secretion. Oncology 56: 169–176, 1999CrossRefPubMedGoogle Scholar
  29. 29.
    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, 2002CrossRefPubMedGoogle Scholar
  30. 30.
    Nannmark U, Basse P, Johansson BR, Kuppen P, Kjergaard J, Hokland M: Morphological studies of effector cell-microvessel interactions in adoptive immunotherapy in tumor-bearing animals. Nat Immun 15: 78–86, 1996–1997Google Scholar
  31. 31.
    ThyagaRajan S, Madden KS, Stevens SY, Felten DL: Anti-tumor 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, 2000CrossRefPubMedGoogle Scholar
  32. 32.
    Lissoni P, Barni S, Tancini G, Rovelli F, Ardizzoia A, Conti A, Maestroni GJ: A study of the mechanisms involved in the immunostimulatory action of the pineal hormone in cancer patients. Oncology 50: 399–402, 1993PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • M. C. Saez
    • 1
  • C. Barriga
    • 1
  • J. J. Garcia
    • 1
  • A. B. Rodriguez
    • 1
  • J. Masot
    • 2
  • E. Duran
    • 2
  • E. Ortega
    • 1
  1. 1.Department of Physiology, Faculty of ScienceUniversity of ExtremaduraBadajozSpain
  2. 2.Histology and Pathological Anatomy Unit, Faculty of Veterinary MedicineUniversity of ExtremaduraCáceresSpain

Personalised recommendations