Cellular and Molecular Life Sciences

, Volume 70, Issue 12, pp 2139–2157 | Cite as

Molecular mechanisms of melatonin’s inhibitory actions on breast cancers

  • Sara Proietti
  • Alessandra Cucina
  • Russel J. Reiter
  • Mariano Bizzarri
Review

Abstract

Melatonin is involved in many physiological functions and it plays an important role in many pathological processes as well. Melatonin has been shown to reduce the incidence of experimentally induced cancers and can significantly inhibit the growth of some human tumors, namely hormone-dependent cancers. The anticancer effects of melatonin have been observed in breast cancer, both in in vivo with models of chemically induced rat mammary tumors, and in vitro studies on human breast cancer cell lines. Melatonin acts at different physiological levels and its antitumoral properties are supported by a set of complex, different mechanisms of action, involving apoptosis activation, inhibition of proliferation, and cell differentiation.

Keywords

Melatonin Breast cancer Epigenetic effects Apoptosis Growth inhibition Cell morphology 

References

  1. 1.
    Hardeland R, Madrid JA, Tal DX et al (2012) Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res 52:139–166PubMedCrossRefGoogle Scholar
  2. 2.
    Cardinali DP, Srinivasan V, Brzezinski A et al (2012) Melatonin and its analogues in insomnia and depression. J Pineal Res 52:167–202CrossRefGoogle Scholar
  3. 3.
    Reiter RJ, Tan DX, Manchester LC et al (2009) Melatonin and reproduction revisited. Biol Reprod 81:445–456PubMedCrossRefGoogle Scholar
  4. 4.
    Rosales-Corral SA, Acuña-Castroviejo D, Coto-Montes A et al (2012) Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202PubMedCrossRefGoogle Scholar
  5. 5.
    Tan DX, Manchester LC, Fuentes-Broto L et al (2011) Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev 12:167–188PubMedCrossRefGoogle Scholar
  6. 6.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ (2012) Melatonin and cardiovascular disease: myth or reality? Rev Esp Cardiol 65:215–218PubMedCrossRefGoogle Scholar
  7. 7.
    Korkmaz A, Ma S, Topal T et al (2012) Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state. Mol Cell Endocrinol 349(2):128–137Google Scholar
  8. 8.
    Sanchez-Barcelo EJ, Mediavilla MD, Tan RJ et al (2010) Scientific basis for the potential use of melatonin in bone diseases: osteoporosis and adolescent idiopathic scoliosis. J Osteoporos ID 830231Google Scholar
  9. 9.
    Dx Tan, Chen LD, Poeggeler B et al (1993) Melatonin: a potent endogenous hydroxyl radical scavenger. Endocr J 1:57–60Google Scholar
  10. 10.
    Hardeland R, Poeggeler B (2008) Melatonin beyond its classical functions. Open Physiol J 1:1–23CrossRefGoogle Scholar
  11. 11.
    Reiter RJ, Paredes SD, Manchester LC et al (2009) Reducing oxidative/nitrosative stress: a newly discovered genre for melatonin. Crit Rev Biochem Mol Biol 44:175–200PubMedCrossRefGoogle Scholar
  12. 12.
    Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16PubMedCrossRefGoogle Scholar
  13. 13.
    Sharman EH, Sharman KG, Bondy SC (2011) Extended exposure to dietary melatonin reduces tumor number and size in aged male mice. Exp Gerontol 46:18–22PubMedCrossRefGoogle Scholar
  14. 14.
    Cutando A, Aneiros-Fernández J, Aneiros-Cachaza J, Arias-Santiago S (2011) Melatonin and cancer: current knowledge and its application to oral cavity tumours. J Oral Pathol Med 40:593–597PubMedCrossRefGoogle Scholar
  15. 15.
    Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ (2012) Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs 21:819–831PubMedCrossRefGoogle Scholar
  16. 16.
    Hill SM, Blask DE, Xiang S et al (2011) Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer. J Mammary Gland Biol Neoplasia. 16:235–245PubMedCrossRefGoogle Scholar
  17. 17.
    Lissoni P, Rovelli F (2012) Principles of psychoneuroendocrinoimmunotherapy of cancer. Immunotherapy 4:77–86PubMedCrossRefGoogle Scholar
  18. 18.
    Zha L, Fan L, Sun G et al (2012) Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress-induced apoptosis. J Pineal Res 52:322–331PubMedCrossRefGoogle Scholar
  19. 19.
    Blask DE (2009) Melatonin, sleep disturbance and cancer risk. Sleep Med Rev 13:252–264CrossRefGoogle Scholar
  20. 20.
    Jung-Hynes B, Reiter RJ, Ahmad N (2010) Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res 48:9–19PubMedCrossRefGoogle Scholar
  21. 21.
    Mediavilla MD, Sanchez-Barcelo EJ, Tan DX (2010) Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem 17:4462–4481PubMedCrossRefGoogle Scholar
  22. 22.
    Greene MW (2012) Circadian rhythms and tumor growth. Cancer Lett 318:115–123PubMedCrossRefGoogle Scholar
  23. 23.
    Blask DE, Dauchy RT, Sauer LA (2005) Putting cancer to sleep at night. Endocrine 27(2):179–188PubMedCrossRefGoogle Scholar
  24. 24.
    Russel JR, Tan DX, Korkmaz A (2007) Light at night, chronodisruption, melatonin suppression, and cancer risk: a review. Crit Rev Oncog 13:303–328CrossRefGoogle Scholar
  25. 25.
    Georgiou E (1929) Über die Natur und die Pathogenese der Krebstumoren, Radikale Heilung des Krebses bei weißen Mäusen. J Cancer Res Clin Oncol (Zeitschrift für Kregsforshung) 28(1):562–572Google Scholar
  26. 26.
    Lapin V, Ebels I (1976) Effects of some low molecular weight sheep pineal fractions and melatonin on different tumours in rats and mice. Oncology 33:110–113PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta D, Attanasio A, Reiter RJ (1988) The pineal gland and cancer brain research promotion. Tübingen, Germany, pp 1–383Google Scholar
  28. 28.
    Cohen M, Lippman M, Chabner B (1978) Role of pineal gland in aetiology and treatment of breast cancer. Lancet 2:814–816PubMedCrossRefGoogle Scholar
  29. 29.
    Srinivasan V, Spence DW, Pandi-Perumal SR et al (2008) Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther 7:189–203PubMedCrossRefGoogle Scholar
  30. 30.
    Villarini A, Pasanisi P, Traina A (2012) Lifestyle and breast cancer recurrences: the DIANA-5 trial. Tumori 98:1–18PubMedGoogle Scholar
  31. 31.
    Adams SV, Newcomb PA, White E (2012) Dietary cadmium and risk of invasive postmenopausal breast cancer in the VITAL cohort. Cancer Causes Control 23:845–854Google Scholar
  32. 32.
    DeVita VT Jr, Rosenberg SA (2012) Two hundred years of cancer research. N Engl J Med 366:2207–2214PubMedCrossRefGoogle Scholar
  33. 33.
    Reiter RJ, Tan DX, Erren TC et al (2009) Light-mediated perturbations of circadian timing and cancer risk: a mechanistic analysis. Integr Cancer Ther 8:354–360PubMedCrossRefGoogle Scholar
  34. 34.
    Hansen J, Stevens RG (2011) Night shiftwork and breast cancer risk: overall evidence. Occup Environ Med 68:236–240PubMedCrossRefGoogle Scholar
  35. 35.
    Blask DE, Dauchy RT, Brainard GC et al (2009) Circadian stage-dependent inhibition of human breast cancer metabolism and growth by the nocturnal melatonin signal: consequences of its disruption by light at night in rats and women. Integr Cancer Ther 8:347–353PubMedCrossRefGoogle Scholar
  36. 36.
    Bartsch C, Bartsch H (2006) The anti-tumor activity of pineal melatonin and cancer enhancing life styles in industrialized societies. Cancer Causes Control 17:559–571PubMedCrossRefGoogle Scholar
  37. 37.
    Kerenyi NA, Pandula E, Feuer G (1990) Why the incidence of cancer is increasing: the role of "light pollution". Med Hypotheses 33:75–78PubMedCrossRefGoogle Scholar
  38. 38.
    Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93:1557–1562PubMedCrossRefGoogle Scholar
  39. 39.
    Hansen J (2001) Increased breast cancer risk among women who work predominantly at night. Epidemiology 12:74–77PubMedCrossRefGoogle Scholar
  40. 40.
    Bartsch C, Bartsch H, Jain AK et al (1981) Urinary melatonin levels in human breast cancer patients. J Neural Transm 52:281–294PubMedCrossRefGoogle Scholar
  41. 41.
    Bartsch C, Bartsch H, Bellmann O et al (1991) Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism. Cancer 67:1681–1684PubMedCrossRefGoogle Scholar
  42. 42.
    Falkson G, Falkson HC, Steyn ME et al (1990) Plasma melatonin in patients with breast cancer. Oncology 47:401–405PubMedCrossRefGoogle Scholar
  43. 43.
    Tamarkin L, Cohen M, Roselle D et al (1981) Melatonin inhibition and pinealectomy enhancement of 7–12 dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res 41:4432–4436PubMedGoogle Scholar
  44. 44.
    Blask DE (1984) The pineal: an oncostatic gland? In: Reiter RJ (ed) The pineal gland. Raven Press, New York, pp 253–284Google Scholar
  45. 45.
    Saez MC, Barriga C, Garcia JJ et al (2005) Melatonin increases the survival time of animals with untreated mammary tumours: neuroendocrine stabilization. Mol Cell Biochem 278:15–20PubMedCrossRefGoogle Scholar
  46. 46.
    Sanchez-Barcelo EJ, Cos S, Fernandez R et al (2003) Melatonin and mammary cancer: a short review. Endocr Relat Cancer 10:153–159PubMedCrossRefGoogle Scholar
  47. 47.
    Kubatka P, Bojkova B, Kalicka K et al (2001) Preventive effects of raloxifene and melatonin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats. Neoplasma 48:313–319PubMedGoogle Scholar
  48. 48.
    Pawlikowski M, Winczyk K, Karasek M (2002) Oncostatic action of melatonin: facts and question marks. Neuro Endocrinol Lett 23:24–29PubMedGoogle Scholar
  49. 49.
    Cos S, Mediavilla D, Martinez-Campa C et al (2006) Exposure to light-at-night increases the growth of DMBA-induced mammary adenocarcinomas in rats. Cancer Lett 235:266–271PubMedCrossRefGoogle Scholar
  50. 50.
    Anisimov VN (2003) The role of pineal gland in breast cancer development. Crit Rev Oncol Hematol 46:221–234PubMedCrossRefGoogle Scholar
  51. 51.
    Blask DE, Pellettier DB, Hill SM et al (1991) 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 117:526–532PubMedCrossRefGoogle Scholar
  52. 52.
    Palmer HJ, Paulson KE (1997) Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr Rev 55:353–361PubMedCrossRefGoogle Scholar
  53. 53.
    Cerutti PA (1985) Prooxidant states and tumor promotion. Science 227:375–381PubMedCrossRefGoogle Scholar
  54. 54.
    Reiter RJ, Tan DX, Terron M et al (2007) Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochim Pol 54:1–9PubMedGoogle Scholar
  55. 55.
    Burns JK (1973) Administration of melatonin to non-human primates and to women with breast carcinoma. J Physiol 229:38–39Google Scholar
  56. 56.
    Di Bella L, Scalera G, Rossi MT (1979) Perspectives in pineal function. Prog Brain Res 52:475–478PubMedCrossRefGoogle Scholar
  57. 57.
    Lissoni P, Barni S, Meregalli S et al (1995) Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 71:854–856PubMedCrossRefGoogle Scholar
  58. 58.
    Lissoni P, Barni S, Cattaneo G et al (1991) Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 48:448–450PubMedCrossRefGoogle Scholar
  59. 59.
    Lissoni P, Barni S, Tancini G et al (1994) 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 69:196–199PubMedCrossRefGoogle Scholar
  60. 60.
    Lissoni P, Barni S, Ardizzoia A et al (1994) A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 73:699–701PubMedCrossRefGoogle Scholar
  61. 61.
    Lissoni P, Barni S, Ardizzoia A et al (1992) Randomized study with the pineal hormone melatonin versus supportive care alone in advanced non small cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology 49:336–339PubMedCrossRefGoogle Scholar
  62. 62.
    Lissoni P, Barni S, Crispino S et al (1989) Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol 25:789–795PubMedCrossRefGoogle Scholar
  63. 63.
    Lissoni P, Barni S, Tancini G et al (1987) Clinical study of melatonin in untreatable advanced cancer patients. Tumori 73:475–480PubMedGoogle Scholar
  64. 64.
    Panzer A, Viljioen M (1997) The validity of melatonin as an oncostatic agent. J Pineal Res 22:184–207PubMedCrossRefGoogle Scholar
  65. 65.
    Mills E, Wu P, Seely D, Guyatt G (2005) Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 39:360–366PubMedCrossRefGoogle Scholar
  66. 66.
    Bartsch C, Bartsch H, Karasek M (2002) Melatonin in clinical oncology. Neuro Endocrinol Lett 23(1):30–38PubMedGoogle Scholar
  67. 67.
    Hill SM, Blask DE (1988) Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 48:6121–6126PubMedGoogle Scholar
  68. 68.
    Cos S, Blask DE, Lemus-Wilson A et al (1991) Effects of melatonin on the cell cycle kinetics and oestrogen rescue of MCF-7 human breast cancer cells in culture. J Pineal Res 10:36–42PubMedCrossRefGoogle Scholar
  69. 69.
    Cos S, Recio J, Sanchez-Barcelo EJ (1996) Modulation of the cell cycle time of MCF-7 human breast cancer cells by melatonin. Life Sci 58:811–816PubMedCrossRefGoogle Scholar
  70. 70.
    Cucina A, Proietti S, D’Anselmi F et al (2009) Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. J Pineal Res 46:172–180PubMedCrossRefGoogle Scholar
  71. 71.
    L’hermite-Baleriaux M, L’hermite M, Pasteels JM et al (1990) Effect of melatonin on the proliferation of human mammary cancer cell lines. Endocr Soc 140:59Google Scholar
  72. 72.
    Molis T, Muraoka HG, Castles C et al (1991) Growth regulatory effects of melatonin are linked to the oestrogen response pathway of human breast cancer cells. Endocr Soc 588:177Google Scholar
  73. 73.
    Shellard SA, Whelan RDH, Hill BT (1989) Growth inhibitory and cytotoxic effects of melatonin and its metabolites on human tumour cell lines in vitro. Br J Cancer 60:288–290PubMedCrossRefGoogle Scholar
  74. 74.
    Bizzarri M, Cucina A, Valente MG et al (2003) Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures. J Surg Res 110:332–337PubMedCrossRefGoogle Scholar
  75. 75.
    Cos S, Fernandez F, Sanchez-Barcelo EJ (1996) Melatonin inhibits DNA synthesis in MCF-7 human breast cancer cells in vitro. Life Sci 58:2447–2453PubMedCrossRefGoogle Scholar
  76. 76.
    Cos S, Sanchez-Barcelo EJ (2000) Melatonin and mammary pathological growth. Front Neuroendocrinol 21:133–170PubMedCrossRefGoogle Scholar
  77. 77.
    Hill SM, Spriggs LL, Simon MA et al (1992) The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett 64:249–256PubMedCrossRefGoogle Scholar
  78. 78.
    Dauchy RT, Dauchy EM, Sauer LA et al (2004) Differential inhibition of fatty acid transport in tissue-isolated steroid receptor negative human breast cancer xenografts perfused in situ with isomers of conjugated linoleic acid. Cancer Lett 209:7–15PubMedCrossRefGoogle Scholar
  79. 79.
    Blask DE (1993) Melatonin in oncology. In: Yu HS, Reiter RJ (eds) Melatonin. Biosynthesis, physiological effects, and clinical applications. CRC Press, Boca Raton, pp 447–475Google Scholar
  80. 80.
    Brydon L, Roka F, Petit L (1999) Dual signaling of human Me11a melatonin receptors via Gi2, Gi3 and Gq/11 proteins. Mol Endocrinol 13:2025–2038PubMedCrossRefGoogle Scholar
  81. 81.
    Dubocovich ML, Markowska M (2005) Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2:101–110CrossRefGoogle Scholar
  82. 82.
    Ram PT, Dai J, Yuan L et al (2002) Involvement of the mt1 melatonin receptor in human breast cancer. Cancer Lett 179:141–150PubMedCrossRefGoogle Scholar
  83. 83.
    Roka F, Brydon L, Waldhoer M (1999) Tight association of the human Mel (1a)-melatonin receptor and G (i): precoupling and constitutive activity. Mol Pharmacol 56:1014–1024PubMedGoogle Scholar
  84. 84.
    Dubocovich ML (1988) Luzindole (N-0774): a novel melatonin receptor antagonist. J Pharmacol Exp Ther 246:902–910PubMedGoogle Scholar
  85. 85.
    Dubocovich ML, Masana MI, Iacob S et al (1997) Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn Schmiedebergs Arch Pharmacol 355:365–375PubMedCrossRefGoogle Scholar
  86. 86.
    Collins A, Yuan L, Kiefer TL et al (2003) Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumour formation in nude mice. Cancer Lett 189:49–57PubMedCrossRefGoogle Scholar
  87. 87.
    Yuan L, Collins AR, Dai J et al (2002) MT1 melatonin receptor overexpression enhances the growth suppressive effects of melatonin in human breast cancer cells. Mol Cell Endocrinol 192:147–156PubMedCrossRefGoogle Scholar
  88. 88.
    Jawed S, Kim B, Ottenhof T et al (2007) 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 560:17–22PubMedCrossRefGoogle Scholar
  89. 89.
    Bahia H, Ashman JN, Cawkwell L et al (2002) Karyotypic variation between independently cultured strains of the cell line MCF-7 identified by multicolour fluorescence in situ hybridization. Int J Oncol 20:489–494PubMedGoogle Scholar
  90. 90.
    Hill SM, Cheng C, Yuan L et al (2011) Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin. Breast Cancer Res Treat 127:91–98PubMedCrossRefGoogle Scholar
  91. 91.
    Lai L, Yuan L, Chen Q et al (2008) The Gαi and Gαq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation. J Pineal Res 45:476–488PubMedCrossRefGoogle Scholar
  92. 92.
    Lai L, Yuan L, Cheng Q et al (2009) Alteration of the MT1 melatonin receptor gene and its expression in primary human breast tumors and breast cancer cell lines. Breast Cancer Res Treat 118:293–305PubMedCrossRefGoogle Scholar
  93. 93.
    Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N et al (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol 351:152–166PubMedCrossRefGoogle Scholar
  94. 94.
    Pandi-Perumal SR, Trakht I, Srinivasan V et al (2008) Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 85:335–353Google Scholar
  95. 95.
    Guerrero HY, Gauer F, Schuster C et al (2000) Melatonin regulates the mRNA expression of the mt1 melatonin receptor in the rat pars tuberalis. Neuroendocrinology 71:163–169PubMedCrossRefGoogle Scholar
  96. 96.
    Gerdin MJ, Masana MI, Ren D et al (2003) Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 melatonin receptors. J Pharmacol Exp Ther 304:931–939PubMedCrossRefGoogle Scholar
  97. 97.
    Baldwin SW, Travlos GS, Risinger JI et al (1998) Melatonin does not inhibit estradiol-stimulated proliferation in MCF-7 and BG-1 cells. Carcinogenesis 19:1895–1900PubMedCrossRefGoogle Scholar
  98. 98.
    Reiter RJ, Tan DX, Manchester LC et al (2007) Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci 52:11–28PubMedGoogle Scholar
  99. 99.
    Bonnefont-Rousselot D, Collin F, Jore D, Gardès-Albert M (2011) Reaction mechanism of melatonin oxidation by reactive oxygen species in vitro. J Pineal Res 50:328–335PubMedCrossRefGoogle Scholar
  100. 100.
    Kilic U, Yilmaz B, Ugur M et al (2012) Evidence that membrane-bound G protein-coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral ischemia. J Pineal Res 52:228–235PubMedCrossRefGoogle Scholar
  101. 101.
    Tan DX, Manchester LC, Hardeland R et al (2003) Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res 34:75–78PubMedCrossRefGoogle Scholar
  102. 102.
    Hill SM, Blask DE (1986) Melatonin inhibition of MCF-7 breast cancer cell proliferation: influence of serum factors prolactin and oestradiol. Abstr Endocr Soc 863:246Google Scholar
  103. 103.
    Cos S, Sanchez-Barcelo EJ (1995) Melatonin inhibition of MCF-7 human breast cancer cells: influence of cell proliferation rate. Cancer Lett 93:207–212PubMedCrossRefGoogle Scholar
  104. 104.
    Cos S, Sanchez-Barcelo EJ (1994) Differences between pulsatile or continuous exposure to melatonin on MCF-7 human breast cancer cell proliferation. Cancer Lett 85:105–109PubMedCrossRefGoogle Scholar
  105. 105.
    Cos S, Blask DE (1990) Effects of melatonin on the anchorage-independent growth of human breast cancer cells (MCF-7) in a clonogenic culture system. Cancer Lett 50:115–119PubMedCrossRefGoogle Scholar
  106. 106.
    Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C (2012) Breast cancer therapy based on melatonin. Recent Pat Endocr Metab Immune Drug Discov 1(6):108–116CrossRefGoogle Scholar
  107. 107.
    Reiter RJ, Fraschini F (1969) Endocrine aspects of the mammalian pineal gland: a review. Neuroendocrinology 5:219–255PubMedCrossRefGoogle Scholar
  108. 108.
    Reiter RJ (1980) The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1:109–131PubMedCrossRefGoogle Scholar
  109. 109.
    Barrett P, Bolborea M (2012) Molecular pathways involved in seasonal body weight and reproductive responses governed by melatonin. J Pineal Res 52:376–388PubMedCrossRefGoogle Scholar
  110. 110.
    Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ et al (2003) Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 8:1093–1108CrossRefGoogle Scholar
  111. 111.
    Cohen M, Lippman M, Chabner B (1978) Role of pineal gland in aetiology and treatment of breast cancer. Lancet 2:814–816PubMedCrossRefGoogle Scholar
  112. 112.
    Tamura H, Nakamura Y, Terron MP (2008) Melatonin and pregnancy in the human. Reprod Toxicol 25:291–303PubMedCrossRefGoogle Scholar
  113. 113.
    Tamura H, Nakamura Y, Korkmaz A et al (2009) Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril 92:328–343PubMedCrossRefGoogle Scholar
  114. 114.
    Kauppila A, Kivela A, Pakarinen A et al (1987) Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metab 65:823–828PubMedCrossRefGoogle Scholar
  115. 115.
    Aleandri V, Spina V, Morini A (1996) The pineal gland and reproduction. Hum Reprod Update 2:225–235PubMedCrossRefGoogle Scholar
  116. 116.
    Luboshitzky R, Lavie P (1999) Melatonin and sex hormone interrelationships: a review. J Pediatr Endocrinol Metab 12:355–362PubMedCrossRefGoogle Scholar
  117. 117.
    Woo MM, Tai CJ, Kang SK et al (2001) Direct action of melatonin in human granulosa-luteal cells. J Clin Endocrinol Metab 86:4789–4797PubMedCrossRefGoogle Scholar
  118. 118.
    Soares JM, Masana MI, Ersahin C et al (2003) Functional melatonin receptors in rat ovaries at various stages of the estrous cycle. J Pharmacol Exp Ther 306:694–702PubMedCrossRefGoogle Scholar
  119. 119.
    Sanchez-Barcelo EJ, Cos S, Mediavilla D et al (2005) Melatonin–estrogen interactions in breast cancer. J Pineal Res 38:217–222PubMedCrossRefGoogle Scholar
  120. 120.
    Ram PT, Yuan L, Dai J et al (2000) Differential responsiveness of MCF-7 human breast cancer cell line stocks to the pineal hormone melatonin. J Pineal Res 28:210–218PubMedCrossRefGoogle Scholar
  121. 121.
    Del Rio B, Garcia Pedrero JM, Martinez-Campa C et al (2004) Melatonin an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem 279:38294–38302PubMedCrossRefGoogle Scholar
  122. 122.
    Cos S, Fernandez R, Guezmes A et al (1998) Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res 58:4383–4390PubMedGoogle Scholar
  123. 123.
    Wilson ST, Blask DE, Lemus-Wilson AM (1992) Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro. J Clin Endocrinol Metab 75:669–670PubMedCrossRefGoogle Scholar
  124. 124.
    Mediavilla MD, Guezmez A, Ramos S et al (1997) Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene. J Pineal Res 22:86–94PubMedCrossRefGoogle Scholar
  125. 125.
    Kiefer TL, Lai L, Yuan L et al (2005) Differential regulation of estrogen receptor alpha, glucocorticoid, receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins. J Pineal Res 38:231–239PubMedCrossRefGoogle Scholar
  126. 126.
    Garcia-Rato A, Garcia-Pedrero JM, Martinez MA et al (1999) Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J 13:857–868Google Scholar
  127. 127.
    Lawson NO, Wee BE, Blask DE et al (1992) Melatonin decreases estrogen receptor expression in the medial preoptic area of inbred (LSH/SsLak) golden hamsters. Biol Reprod 47:1082–1090PubMedCrossRefGoogle Scholar
  128. 128.
    Ram PT, Dai J, Yuan L et al (2002) Involvement of the mt1 melatonin receptor in human breast cancer. Cancer Lett 179:141–150PubMedCrossRefGoogle Scholar
  129. 129.
    Mangelsdorf DJ, Thummel C, Beato M et al (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  130. 130.
    Glass CK, Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14:121–141PubMedGoogle Scholar
  131. 131.
    Benoit G, Cooney A, Giguere V et al (2006) International Union of Pharmacology LXVI. Orphan nuclear receptors. Pharmacol Rev 58:798–836PubMedCrossRefGoogle Scholar
  132. 132.
    Mukherjee R, Davies PJ, Crombie DL et al (1997) Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386:407–410PubMedCrossRefGoogle Scholar
  133. 133.
    Mukherjee R, Jow L, Croston GE et al (1997) Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 272:8071–8076PubMedCrossRefGoogle Scholar
  134. 134.
    Mckenna NJ, O’Malley BW (2002) Minireview: nuclear receptor coactivators—an update. Endocrinology 143:2461–2465PubMedCrossRefGoogle Scholar
  135. 135.
    Mckenna NJ, O’Malley BW (2002) Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465–474PubMedCrossRefGoogle Scholar
  136. 136.
    Becker-Andre M, Wiesemberg I, Schaeren-Wiemers N et al. (1994) Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem 269:28531–28534Google Scholar
  137. 137.
    Agez L, LaurentV Pevet P et al (2007) Melatonin affects nuclear orphan receptors mRNA in the rat suprachiasmatic nuclei. Neuroscience 144:522–530PubMedCrossRefGoogle Scholar
  138. 138.
    Park HT, Baek SY, Kim BS et al (1996) Developmental expression of ‘RZR beta, a putative nuclear-melatonin receptor’ mRNA in the suprachiasmatic nucleus of the rat. Neurosci Lett 217:17–20PubMedCrossRefGoogle Scholar
  139. 139.
    Baler R, Coon S, Klein DC (1996) Orphan nuclear receptor RZRbeta: cyclic AMP regulates expression in the pineal gland. Biochem Biophys Res Commun 220:975–978PubMedCrossRefGoogle Scholar
  140. 140.
    Naji L, Carillo-Vico A, Guerrero JM et al (2004) Expression of membrane and nuclear melatonin receptors in mouse peripheral organs. Life Sci 74:2227–2236PubMedCrossRefGoogle Scholar
  141. 141.
    Bordji K, Grillasca JP, Gouze JN et al (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes. J Biol Chem 275:12243–12250PubMedCrossRefGoogle Scholar
  142. 142.
    Smirnov AN (2001) Nuclear melatonin receptors. Biochemistry 66:19–26PubMedGoogle Scholar
  143. 143.
    Sharma R, Ottenhof T, Rzeczkowska PA et al (2008) Epigenetic targets for melatonin: induction of histone H3 hyperacetylation and gene expression in C17.2 neural stem cells. J Pineal Res 45:277–284PubMedCrossRefGoogle Scholar
  144. 144.
    Korkmaz A, Sanchez-Barcelo EJ, Tan DX et al (2009) Role of melatonin in the epigenetic regulation of breast cancer. Breast Cancer Res Treat 115:13–27PubMedCrossRefGoogle Scholar
  145. 145.
    Korkmaz A (2009) Epigenetic actions of melatonin. J Pineal Res 46:117–118PubMedCrossRefGoogle Scholar
  146. 146.
    Korkmaz A, Tamura H, Manchester LC et al (2009) Combination of melatonin and a peroxisome proliferator-activated receptor-gamma agonist induces apoptosis in a breast cancer cell line. J Pineal Res 46:115–116PubMedCrossRefGoogle Scholar
  147. 147.
    Aronika SM, Kraus WL, Katzenellenbogen BS (1994) Oestrogen action via the cAMP signalling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 91:8517–8521CrossRefGoogle Scholar
  148. 148.
    Kiefer T, Ram PT, Yuan L, Hill SM (2002) Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells. Breast Cancer Res Treat 71:37–45PubMedCrossRefGoogle Scholar
  149. 149.
    Ram PT, Kiefer T, Silverman M et al (1998) Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. Mol Cell Endocrinol 141:53–64PubMedCrossRefGoogle Scholar
  150. 150.
    Benítez-King G, Ríos A, Martínez A et al (1996) In vitro inhibition of Ca2+/calmodulin-dependent kinase II activity by melatonin. Biochim Biophys Acta 1290:191–196PubMedCrossRefGoogle Scholar
  151. 151.
    Pozo D, Reiter RJ, Calvo JR et al (1997) Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin. J Cell Biochem 1(65):430–442CrossRefGoogle Scholar
  152. 152.
    Soto-Vega E, Ramírez-Rodríguez G, Benitez-King G (2004) Melatonin stimulates calmodulin phosphorylation by protein kinase C. J Pineal Res 37:98–106PubMedCrossRefGoogle Scholar
  153. 153.
    Garcia-Pedrero JM, Martinez MA, Del Rio B et al (2002) Calmodulin is a selective modulator of estrogen receptors. Mol Endocrinol 16:947–960PubMedCrossRefGoogle Scholar
  154. 154.
    Dai J, Inscho EW, Yuan L et al (2002) Modulation of intracellular calcium and calmodulin by melatonin in MCF-7 human breast cancer cells. J Pineal Res 32:112–119PubMedCrossRefGoogle Scholar
  155. 155.
    Li Z, Kim SH, Higgins JMG et al (1999) IQGAP1 and calmodulin modulate E-cadherin function. J Biol Chem 274:37885–37892PubMedCrossRefGoogle Scholar
  156. 156.
    Blask DE (1997) Systemic, cellular and molecular aspects of melatonin action on experimental breast carcinogenesis. In: Stevens RG, Wilson BW, Anderson LE (eds) The melatonin hypothesis-breast cancer and use of electric power. Battel Press, Columbus, p 189–230Google Scholar
  157. 157.
    Blask DE, Wilson ST, Zalatan F (1997) Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated Pathway. Cancer Res 57:1909–1914PubMedGoogle Scholar
  158. 158.
    Leung MF, Chov IN (1989) Relationship between l-chloro-2,4-diitrobenzene induced cytoskeletal perturbations and cellular glutathione. Cell Biol Toxicol 5:51–99PubMedCrossRefGoogle Scholar
  159. 159.
    Benitez-King G, Anton-Tay F (1993) Calmodulin mediates melatonin cytoskeletal effects. Experientia 49:635–641PubMedCrossRefGoogle Scholar
  160. 160.
    Roth JA, Rabin R, Agnello K (1997) Melatonin suppression of PC12 cell growth and death. Brain Res 768:63–70PubMedCrossRefGoogle Scholar
  161. 161.
    Yang QH, Xu YN, Xu RK et al (2007) Antiproliferative effects of melatonin on the growth of rat pituitary prolactin-secreting tumor cells in vitro. J Pineal Res 42:172–179PubMedCrossRefGoogle Scholar
  162. 162.
    Zhou D, Clarke P, Wang J et al (1996) Identification of a promoter that controls aromatase expression in human breast cancer and adipose stromal cells. J Biol Chem 271:15194–15202PubMedCrossRefGoogle Scholar
  163. 163.
    Michael MD, Michael LF, Simpson ER (1997) A CRE-like sequence that binds CREB and contributes to cAMP-dependent regulation of the proximal promoter of the human aromatase P450 (CYP19) gene. Mol Cell Endocrinol 134:147–156PubMedCrossRefGoogle Scholar
  164. 164.
    Zhao Y, Aagarwal VR, Mendelson CR et al (1996) Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology 137:5739–5742PubMedCrossRefGoogle Scholar
  165. 165.
    Cardinali DP, Bonanni Rey RA et al (1992) Diurnal changes in cyclic nucleotide response to pineal indoles in murine mammary glands. J Pineal Res 13:111–116PubMedCrossRefGoogle Scholar
  166. 166.
    Cos S, Martinez-Campa C, Mediavilla MD et al (2005) Melatonin modulates aromatase activity in MCF-7 human breast cancer cells. J Pineal Res 38:136–142PubMedCrossRefGoogle Scholar
  167. 167.
    Gonzalez A, Martinez-Campa C, Mediavilla MD et al (2007) Effects of MT1 melatonin receptor overexpression on the aromatase-suppressive effect of melatonin in MCF-7 human breast cancer cells. Oncol Rep 17:947–953PubMedGoogle Scholar
  168. 168.
    Martinez- Campa C, Gonzalez A, Mediavilla MD et al (2005) Melatonin enhances the inhibitory effect of aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells. Breast Cancer Res Treat 94:249–254PubMedCrossRefGoogle Scholar
  169. 169.
    Ryde CM, Nicholls JE, Dowsett M (1992) Steroid and growth factor modulation of aromatase activity in MCF-7 and T47D breast carcinoma cell lines. Cancer Res 52:1411–1415PubMedGoogle Scholar
  170. 170.
    Cos S, Blask DE (1994) Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J Pineal Res 17:25–32PubMedCrossRefGoogle Scholar
  171. 171.
    Martinez-Campa C, Gonzalez A, Mediavilla MD et al (2009) Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells. Br J Cancer 101:1613–1619PubMedCrossRefGoogle Scholar
  172. 172.
    Suzuki T, Miki Y, Nakamura Y et al (2005) Sex steroid-producing enzymes in human breast cancer. Endocr Relat Cancer 12:701–720PubMedCrossRefGoogle Scholar
  173. 173.
    Suzuki T, Miki Y, Nakata T et al (2003) Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast cancer. J Steroid Biochem Mol Biol 86:449–454PubMedCrossRefGoogle Scholar
  174. 174.
    Gonzalez A, Cos S, Martinez-Campa C et al (2008) Selective estrogen enzyme modulator actions of melatonin in human breast cancer cells. J Pineal Res 45:86–92PubMedCrossRefGoogle Scholar
  175. 175.
    Cai Z, Kwintkiewicz J, Young ME et al (2007) Prostaglandin E2 increases cyp19 expression in rat granulosa cells: implication of GATA-4. Mol Cell Endocrinol 263:181–189PubMedCrossRefGoogle Scholar
  176. 176.
    Subbaramaiah K, Howe LR, Port ER et al (2006) HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res 66:5504–5511PubMedCrossRefGoogle Scholar
  177. 177.
    Dong WG, Mei Q, Yu JP et al (2003) Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol 9:1307–1311PubMedGoogle Scholar
  178. 178.
    Mrnka L, Hock M, Rybova M et al (2008) Melatonin inhibits prostaglandin E2 and sodium nitroprusside-induced ion secretion in rat distal colon. Eur J Pharmacol 581:164–170PubMedCrossRefGoogle Scholar
  179. 179.
    Deng WG, Tang ST, Tseng HP et al (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108:518–5124PubMedCrossRefGoogle Scholar
  180. 180.
    Mohan N, Sadeghi K, Reiter RJ et al (1995) The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-kappa B. Biochem Mol Biol Int 37:1063–1070PubMedGoogle Scholar
  181. 181.
    Chuang JI, Mohan N, Meltz ML et al (1996) Effect of melatonin on NF-kappa-B DNA-binding activity in the rat spleen. Cell Biol Int 20:687–692PubMedCrossRefGoogle Scholar
  182. 182.
    Esposito E, Iacono A, Muia C et al (2008) Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res 44:78–87PubMedGoogle Scholar
  183. 183.
    Crowe DL, Chandraratna RA (2004) A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands. Breast Cancer Res 6:R546–R555PubMedCrossRefGoogle Scholar
  184. 184.
    Fan W, Yanase T, Morinaga H et al (2005) Activation of peroxisome proliferator-activated receptor-gamma and retinoid X receptor inhibits aromatase transcription via nuclear factor kappa B. Endocrinology 146:85–92PubMedCrossRefGoogle Scholar
  185. 185.
    Molis TM, Spriggs LL, Jupiter Y (1995) Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer. J Pineal Res 18:93–103PubMedCrossRefGoogle Scholar
  186. 186.
    Calnaan DPK, Westley BR, May FEB et al (1999) The trefoil peptide TFF1 inhibits the growth of the human gastric adenocarcinoma cell line AGS. J Pathol 188:312–317CrossRefGoogle Scholar
  187. 187.
    Henry JA, Piggott NH, Mallick UK et al (1990) PNR-2/pS2 immunohistochemical staining in breast cancer: correlation with prognostic factors and endocrine response. Br J Cancer 4:615–622Google Scholar
  188. 188.
    Barnes DM, Gillett CE (1998) Cyclin D1 in breast cancer. Breast Cancer Res Treat 52:1–15PubMedCrossRefGoogle Scholar
  189. 189.
    Cicatiello L, Addeo R, Sasso A (2004) Oestrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/oestrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Mol Cell Biol 24:7260–7274PubMedCrossRefGoogle Scholar
  190. 190.
    Fu M, Wang C, Li Z, Sakamaky T et al (2004) Minireview: cyclin D1: normal and abnormal functions. Endocrinology 145:5439–5447PubMedCrossRefGoogle Scholar
  191. 191.
    Fu M, Rao M, Bouras T et al (2005) Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem 280:16934–16941PubMedCrossRefGoogle Scholar
  192. 192.
    Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRefGoogle Scholar
  193. 193.
    Cini G, Neri B, Pacini A et al (2005) Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects. J Pineal Res 39:12–20PubMedCrossRefGoogle Scholar
  194. 194.
    Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414PubMedCrossRefGoogle Scholar
  195. 195.
    Mediavilla MD, Cos S, Sanchez-Barcelo EJ (1999) Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 65:415–420PubMedCrossRefGoogle Scholar
  196. 196.
    Rimler A, Matzkin H, Zisapel N (1999) Cross talk between melatonin and TGF-1 in human benign prostate epithelial cells. Prostate 40:211PubMedCrossRefGoogle Scholar
  197. 197.
    Molis TM, Priggs LL, Hill SM (1994) Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. Mol Endocrinol 8:1683–1690CrossRefGoogle Scholar
  198. 198.
    Czeczuga-Semeniuk E, Anchim T, Dziecioł J et al (2004) Can transforming growth factor-β1 and retinoids modify the activity of estradiol and antiestrogens in MCF-7 breast cancer cells? Acta Biochim Pol 51:733–745PubMedGoogle Scholar
  199. 199.
    Blask DE, Sauer LA, Dauchy RT (2002) Melatonin as a chronobiotic/anticanceragent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2:113–132PubMedCrossRefGoogle Scholar
  200. 200.
    Leon-Blanco MM, Guerrero JM, Reiter JR et al (2003) Melatonin inhibits telomerase activity in the MCF-7 tumour cell line both in vitro and in vivo. J Pineal Res 35:204–211PubMedCrossRefGoogle Scholar
  201. 201.
    Martinez-Campa CM, Alonso-Gonzalez C, Mediavilla MD et al (2008) Melatonin down-regulates hTERT expression induced by either natural estrogens (17b-estradiol) or metalloestrogens (cadmium) in MCF-7 human breast cancer cells. Cancer Lett 268:272–277PubMedCrossRefGoogle Scholar
  202. 202.
    Leon-Blanco MM, Guerrero JM, Reiter RJ et al (2004) RNA expression of human telomerase subunits TR and TERT is differentially affected by melatonin receptor agonists in the MCF-7 tumor cell line. Cancer Lett 216:73–80PubMedCrossRefGoogle Scholar
  203. 203.
    Blasco MA (2007) The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8:299–309PubMedCrossRefGoogle Scholar
  204. 204.
    Reiter RJ (2004) Mechanisms of cancer inhibition by melatonin. J Pineal Res 37:213–214PubMedCrossRefGoogle Scholar
  205. 205.
    Sainz RM, Mayo JC, Rodriguez C et al (2003) Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60:1407–1426PubMedCrossRefGoogle Scholar
  206. 206.
    Sánchez-Hidalgo M, Guerrero JM, Villegas I (2012) Melatonin, a natural programmed cell death inducer in cancer. Curr Med Chem (in press)Google Scholar
  207. 207.
    Karasek M, Winczyk K, Kunert-Radk J et al (1998) Antiproliferative effects of melatonin and CGP52608 on the murine colon 38 adenocarcinoma in vitro and in vivo. Neuroendocrinol Lett 19:71–78Google Scholar
  208. 208.
    Winczyk K, Pawlikowski M, Lawnicka H et al (2002) Effects of melatonin and melatonin receptors ligand N-[(4-methoxy-1H-indol-2yl) methyl] propanamide on murine Colon 38 cancer growth in vitro and in vivo. Neuroendocrinol Lett 1:50–54Google Scholar
  209. 209.
    Motilva V, García-Mauriño S, Talero E et al (2011) New paradigms in chronic intestinal inflammation and colon cancer: role of melatonin. J Pineal Res 51:44–60PubMedCrossRefGoogle Scholar
  210. 210.
    Carbajo-Pescador S, García-Palomo A, Martín-Renedo J et al (2011) Melatonin modulation of intracellular signaling pathways in hepatocarcinoma HepG2 cell line: role of the MT1 receptor. J Pineal Res 51:463–471PubMedCrossRefGoogle Scholar
  211. 211.
    Garcia-Santos G, Antolin I, Herrera F et al (2006) Melatonin induces apoptosis in human neuroblastoma cancer cells. J Pineal Res 41:130–135PubMedCrossRefGoogle Scholar
  212. 212.
    El-Missiry MA, Abd EL-Aziz AF (2000) Influence of melatonin on proliferation and antioxidant system in Ehrlich ascites carcinoma cells. Cancer Lett 151:119–125PubMedCrossRefGoogle Scholar
  213. 213.
    Rubio S, Estevez F, Cabrera J et al (2007) Inhibition of proliferation and induction of apoptosis by melatonin in human myeloid HL-60 cells. J Pineal Res 42:131–138PubMedCrossRefGoogle Scholar
  214. 214.
    Trubiani O, Recchioni R, Moroni F et al (2005) Melatonin provokes cell death in human B-lymphoma cells by mitochondrial-dependent apoptotic pathway activation. J Pineal Res 39:425–431PubMedCrossRefGoogle Scholar
  215. 215.
    Leja-Szpak A, Jaworek J, Pierzchalski P et al (2010) Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). J Pineal Res 49:248–255PubMedCrossRefGoogle Scholar
  216. 216.
    Gonzalez A, del Castillo-Vaquero A, Miro-Moran A et al (2011) Melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology. J Pineal Res 50:250–260PubMedCrossRefGoogle Scholar
  217. 217.
    Um HJ, Park JW, Kwon TK (2011) Melatonin sensitizes Caki renal cancer cells to kahweol-induced apoptosis through CHOP-mediated up-regulation of PUMA. J Pineal Res 50:359–366PubMedCrossRefGoogle Scholar
  218. 218.
    Wolfler A, Caluba HC, Abuja PM et al (2001) Prooxidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells. FEBS Lett 502:127–131PubMedCrossRefGoogle Scholar
  219. 219.
    Bejarano I, Espino J, Barriga C et al (2011) Pro-oxidant effect of melatonin in tumour leucocytes: relation with its cytotoxic and pro-apoptotic effects. Basic Clin Pharmacol Toxicol 108:14–20PubMedCrossRefGoogle Scholar
  220. 220.
    Casado-Zapico S, Martín V, García-Santos G et al (2011) Regulation of the expression of death receptors and their ligands by melatonin in haematological cancer cell lines and in leukaemia cells from patients. J Pineal Res 50:345–355PubMedCrossRefGoogle Scholar
  221. 221.
    Cos S, Mediavilla MD, Fernandez R et al (2002) Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro? J Pineal Res 32:90–96PubMedCrossRefGoogle Scholar
  222. 222.
    Czeczuga-Semeniuk E, Wołczyński S, Anchim T et al (2002) Effect of melatonin and all-trans retinoic acid on the proliferation and induction of the apoptotic pathway in the culture of human breast cancer cell line MCF-7. Pol J Pathol 53:59–65PubMedGoogle Scholar
  223. 223.
    Eck-Enriquez KM, Yuan L, Duffy L et al (1998) A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. Br J Cancer 77:2129–2137CrossRefGoogle Scholar
  224. 224.
    Eck-Enriquez KM, Kiefer TL, Spriggs LL et al (2000) Pathways through which a regimen of melatonin and retinoic acid induces apoptosis in MCF-7 human breast cancer cells. Breast Cancer Res Treat 61:229–239PubMedCrossRefGoogle Scholar
  225. 225.
    Abd El-Aziz MA, Hassan HA, Mohamed MH et al (2005) The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model. Int J Exp Pathol 86:383–396CrossRefGoogle Scholar
  226. 226.
    Momand J, Wu HH, Dasgupta G (2000) MDM2–master regulator of the p53 tumor suppressor protein. Gene 242:15–29PubMedCrossRefGoogle Scholar
  227. 227.
    RozieresS DE, Maya R, Oren M et al (2000) The loss of MDM2 induces p53-mediated apoptosis. Oncogene 19:1691–1697CrossRefGoogle Scholar
  228. 228.
    Inoue T, Geyer RK, Yu ZK et al (2001) Downregulation of MDM2 stabilizes p53 by inhibiting p53 ubiquitination in response to specific alkylating agents. FEBS Lett 490:196–201PubMedCrossRefGoogle Scholar
  229. 229.
    Proietti S, Cucina A, D’Anselmi F et al (2011) Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. J Pineal Res 50:150–158PubMedGoogle Scholar
  230. 230.
    Lopez-Burillo S, Tan DX, Mayo JC et al (2003) Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and a-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions. J Pineal Res 34:269–277PubMedCrossRefGoogle Scholar
  231. 231.
    Mao L, Yuan L, Hill SM. Inhibition of cell proliferation and blockade of cell invasion by melatonin in human breast cancer cells mediated through multiple signaling pathways. Paper presented at: 97th annual meeting of the American Association for Cancer Research 2006 Washington, DC. Abstract 495Google Scholar
  232. 232.
    Cos S, Fernandez R (2000) Melatonin effects on intercellular junctional communication in MCF-7 human breast cancer cells. J Pineal Res 29:166–171PubMedCrossRefGoogle Scholar
  233. 233.
    Trosko JE, Chang CC, Madhukar BV et al (1990) Chemical, oncogene and growth factor inhibition of gap junctional intercellular communication: an integrative hypothesis of carcinogenesis. Pathobiology 58:265–278PubMedCrossRefGoogle Scholar
  234. 234.
    Hamada J, Takeichi N, Kobayashi H (1987) Inverse correlation between the metastatic capacity of cell clones derived from a rat mammary carcinoma and their intercellular communication with normal fibroblasts. Gann 78:1175–1178PubMedGoogle Scholar
  235. 235.
    Crespo D, Fernandez-Viadero C, Verdura R et al (1994) Interaction between melatonin and estradiol on morphological and morphometric features of MCF-7 human breast cancer cells. J Pineal Res 16:215–222PubMedCrossRefGoogle Scholar
  236. 236.
    Swarnakar R, Paul S, Singh LP et al (2011) Matrix metalloproteinases in health and disease: regulation by melatonin. J Pineal Res 50:8–20PubMedCrossRefGoogle Scholar
  237. 237.
    Sainz RM, Mayo JC, Tan DX et al (2005) Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate 63:29–43PubMedCrossRefGoogle Scholar
  238. 238.
    Rodriguez-Garcia A, Mayo JC, Heria D et al (2012) Phenotypic changes caused by melatonin increased sensitivity of prostate cancer cells to cytokine-induced apoptosis. J Pineal Res (in press)Google Scholar
  239. 239.
    Roberts K (1974) Cytoplasmic microtubules and their functions. Prog Biophys Mol Biol 28:371–420PubMedCrossRefGoogle Scholar
  240. 240.
    Ingber DE (2003) Tensegrity, II. How structural networks influence cellular information processing networks. J Cell Sci 116:1397–1408PubMedCrossRefGoogle Scholar
  241. 241.
    Wang N, Tytell JD, Ingber DE (2009) Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nature Rev Mol Cell Biol 10:75–82CrossRefGoogle Scholar
  242. 242.
    Pourati J, Maniotis A, Speigel DM et al (1998) Is cytoskeletal tension a major determinant of cell deformability in adherent endothelial cells? Am J Physiol 274:C1283–C1289PubMedGoogle Scholar
  243. 243.
    Hammond TG, Lewis FC, Goodwin TJ et al (1999) Gene expression in space. Nat Med 5:359PubMedCrossRefGoogle Scholar
  244. 244.
    Stein GS, Van Wijnen AJ, Stein JL et al (1999) Implications for interrelationships between nuclear architecture and control of gene expression under microgravity conditions. FASEB 13:S157–S166Google Scholar
  245. 245.
    Chen CS, Mrksich M, Huang S et al (1997) Geometric control of cell life and death. Science 276:1425–1428PubMedCrossRefGoogle Scholar
  246. 246.
    Huang S, Ingber DE (2000) Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks. Exp Cell Res 261:91–103PubMedCrossRefGoogle Scholar
  247. 247.
    D’Anselmi F, Valerio MC, Cucina A et al (2011) Metabolism and cell shape in cancer: a fractal analysis. Int J Biochem Cell Biol 43:1052–1058PubMedCrossRefGoogle Scholar
  248. 248.
    Raz A, Geiger B (1982) Altered organization of cell-substrate contacts and membrane-associated cytoskeleton in tumor cell variants exhibiting different metastatic capabilities. Cancer Res 42:5183–5190PubMedGoogle Scholar
  249. 249.
    Benitez-King G, Tunez I, Bellon A et al (2003) Melatonin prevents cytoskeletal alterations and oxidative stress induced by okadaic acid in N1E−115 cells. Exp Neurol 182:151–159PubMedCrossRefGoogle Scholar
  250. 250.
    Wang LH (2004) Molecular signaling regulating anchorage independent growth of cancer cells. Mt Sinai J Med 71:361–367PubMedGoogle Scholar
  251. 251.
    Bharadwaj S, Thanawala R, Bon G et al (2005) Resensitization of breast cancer cells to anoikis by tropomyosin-1: role of Rho kinase-dependent cytoskeleton and adhesion. Oncogene 24:8291–8303PubMedCrossRefGoogle Scholar
  252. 252.
    Raftopoulou M, Hall A (2004) Cell migration: Rho GTPases lead the way. Dev Biol 265:23–32PubMedCrossRefGoogle Scholar
  253. 253.
    Huerto-Delgadillo L, Anton-Tay F, Benitez-King G (1994) Effects of melatonin on microtubule assembly depend on hormone concentration: role of melatonin as a calmodulin antagonist. J Pineal Res 17:55–62PubMedCrossRefGoogle Scholar
  254. 254.
    Benitez-King G, Soto-Vega E, Ramirez-Rodriguez G (2009) Melatonin modulates microfilament phenotypes in cancer cells: implications for adhesion and inhibition of cancer cell migration. Histol Histopathol 24:789–799PubMedGoogle Scholar
  255. 255.
    Ortiz-Lopez L, Morales-Mulia S, Ramiraz-Rodriguez G et al (2009) ROCK-regulated cytoskeletal dynamics participate in the inhibitory effect of melatonin on cancer cell migration. J Pineal Res 46:15–21PubMedCrossRefGoogle Scholar
  256. 256.
    Ramirez-Rodriguez G, Meza I, Hernandez ME et al (2003) Melatonin induced cyclic modulation of vectorial water transport in kidney-derived MDCK cells. Kidney Int 63:1356–1364PubMedCrossRefGoogle Scholar
  257. 257.
    Ramirez-Rodriguez G, Ortiz-Lopez L, Benitez-King G (2007) Melatonin increases stress fibers and focal adhesions in MDCK cells: participation of Rho-associated kinase and protein kinase C. J Pineal Res 42:180–190PubMedCrossRefGoogle Scholar
  258. 258.
    Yuan J, Shi GX, Shao Y et al (2008) Calmodulin bound to stress fibers but not microtubules involves regulation of cell morphology and motility. Int J Biochem Cell Biol 40:284–293PubMedCrossRefGoogle Scholar
  259. 259.
    Benitez-King G (2006) Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 40:1–9PubMedCrossRefGoogle Scholar
  260. 260.
    Lee SE, Kim SJ, Youn JP et al (2011) MicroRNA and gene expression analysis of melatonin-exposed human breast cancer cell lines indicating involvement of the anticancer effect. J Pineal Res 51:345–352PubMedCrossRefGoogle Scholar
  261. 261.
    Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C et al (2012) Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs 21:819–831PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Sara Proietti
    • 1
    • 2
  • Alessandra Cucina
    • 2
  • Russel J. Reiter
    • 3
  • Mariano Bizzarri
    • 4
  1. 1.Department of Clinical and Molecular MedicineUniversity “La Sapienza”RomeItaly
  2. 2.Department of Surgery “P.Valdoni”University “La Sapienza”RomeItaly
  3. 3.Department of Cellular and Structural BiologyUniversity of Texas Health Science CenterSan AntonioUSA
  4. 4.Systems Biology Group Laboratory, Department of Experimental MedicineUniversity “La Sapienza”RomeItaly

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