Östrojenle indüklenen meme kanseri, tedavi yaklaşımları ve melatoninin tedavideki rolü

Year 2019, Volume: 39 Issue: 2, 113 - 128, 01.06.2019

Elif İnce , Hande Gürer Orhan

Abstract

Supporting Institution

TÜBİTAK

Project Number

117S065

Estrogen-Induced Breast Cancer, Therapeutical Approaches and the Role of Melatonin in Treatment

Abstract

Meme kanseri, dünyada görülme sıklığı hızla artan ve kadınlarda kanserden ölüm nedenleri arasında ikinci sırada yer alan bir kanser türüdür. Endojen östrojenlerin ve bazı eksojen östrojenik bileşiklerin reseptör aracılığıyla hücre proliferasyonunu arttırarak, ya da metabolizmaları sonucu oluşan reaktif kinon metabolitlerinin DNA’ya bağlanması ile meme kanserinin oluşum ve gelişimine katkıda bulunduğu bildirilmektedir. Hormon bağımlı meme kanserinin adjuvan tedavisinde östrojenin etkisini ortadan kaldırmayı amaçlayan mekanizmalar aracılığı ile iki temel terapötik ajan grubu kullanılmaktadır; östrojenin reseptörü aracılığıyla gerçekleşen etkilerini hedef alan selektif östrojen reseptör modülatörleri (SERM) ve östrojen sentezinde yer alan enzimatik yolakları hedef alan selektif östrojen enzim modülatörleri (SEEM). Bu ilaçların çeşitli yan etkilerinin olması ve tedavi sırasında bazı ilaçlara direnç gelişmesi gibi faktörler meme kanseri tedavisinde yeni ajanların geliştirilmesi konusundaki çalışmaların sürmesini desteklemektedir. Endojen bir hormon olan melatoninin hormon-ilişkili meme kanserinde östrojen reseptörü aracılıklı etkileri değiştirdiği ve dokularda lokal östrojen sentezini inhibe ettiği bilinmektedir. Meme kanserinin önlenmesi ve tedavisinde destekleyici ajan olarak kullanımının diğer ilaçların etkinliğini artırdığı ve yan etkilerini azalttığı gösterilmiştir. Bunun yanında düşük yarılanma ömrüne sahip olması ve oral biyoyararlanımının düşük olması melatoninin ilaç olarak kullanımı kısıtlamaktadır. Bu nedenlerle yarılanma ömrü daha uzun ve daha etkin melatonin analoglarının sentezlenmesinin tedavi başarısını artırabileceği tartışılmaktadır.

Keywords

Meme kanseri, , östrojen, SERM, SEEm, Melatonin

Project Number

117S065

References

• 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015, 136(5):E359–86.
• 2. Dorgan JF, Longcope C, Stephenson HE, Falk RT, Miller R, Franz C, Kahle L, Campbell WS, Tangrea JA, Schatzkin A: Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkers 1996, 5(7):533–9.
• 3. Thomas H, Key T, Allen D, Moore J, Dowsett M, Fentiman I, Wang DY: A prospective study of endogenous serum hormone concentrations and breast cancer risk in post-menopausal women on the island of Guernsey. Br J Cancer 1997, 76(3):401–5. 4. Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE: Plasma Sex Steroid Hormone Levels and Risk of Breast Cancer in Postmenopausal Women. JNCI J Natl Cancer Inst 1998, 90(17):1292–9.
• 5. Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE: A Prospective Study of Estradiol and Breast Cancer in Japanese Women 1.Cancer Epidemiol. Biomarkers Prev. 2000, 9:575–79.
• 6. Yue W, Yager JD, Wang JP, Jupe ER, Santen RJ: Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids 2013,78(2):161–70.
• 7. Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkila P, Heikkinen T, Nevanlinna H, Akslen LA, Begin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AW, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MWR, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, Garcia-Closas M, Caldas C, Pharoah PD, Huntsman D: Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: A collaborative analysis of data for 10,159 cases from 12 studies. PLoS Medicine 2010, 7(5): e1000279.
• 8. Perou CM, Surlie T, Eisen MB, van de Rijn M, Jeffreyk SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluges E, Pergamenschikovning A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D: Molecular portraits of human breast tumours. Nature 2000, 406(6797):747–52.
• 9. Reis-Filho JS, Pusztai L: Gene expression profiling in breast cancer: Classification, prognostication, and prediction. The Lancet 2011, 378:1812–23.
• 10. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ: Strategies for subtypes-dealing with the diversity of breast cancer: Highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer. Ann Oncol. 2011, 22(8):1736–47.
• 11. Alteri R, Barnes C, Burke A, Gansler T, Gapstur S, Gaudet M, Kramer J, Newman LA,Niemeyer D, Richards C, Runowicz C, Saslow D, Simpson S, Smith R, Sullivan K, Wagner D, Xu J: Breast Cancer Facts & Figures 2013-2014. Am Cancer Soc 2014;38. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-040951.pdf
• 12. Perou CM, Borresen-Dale A-L: Systems Biology and Genomics of Breast Cancer. Cold Spring Harb Perspect Biol 2011, 3(2):a003293–a003293.
• 13. Simpson ER: Sources of estrogen and their importance. J Steroid Biochem Mol Biol 2003, 86:225–30.
• 14. Clemons M, Goss P: Estrogen and the risk of breast cancer. N Engl J Med 2001, 344(4):276–85.
• 15. Henderson BE, Ross R, Bernstein L: Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 1988, 48(2):246–53.
• 16. Roy D, Abul-Hajj YJ: Estrogen-nucleic acid adducts: Guanine is major site for interaction between 3,4-estrone quinone and COIII gene. Carcinogenesis 1997, 18(6):1247–9.
• 17. Roy D, Cai Q, Felty Q, Narayan S: Estrogen-Induced Generation of Reactive Oxygen and Nitrogen Species, Gene Damage, and Estrogen-Dependent Cancers. J Toxicol Environ Heal Part B 2007, 10(4):235–57.
• 18. Bernstein L, Ross RK: Endogenous Hormones and Breast Cancer Risk. Epidemiol Rev 1993, 15(1):48–65.
• 19. Xu W-H, Xiang Y-B, Ruan Z-X, Zheng W, Cheng J-R, Dai Q, Gao, Y-T, Shu, X-O: Menstrual and reproductive factors and endometrial cancer risk: Results from a population-based case-control study in urban Shanghai. Int J Cancer 2004, 108(4):613-9.
• 20. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet (London, England) 1996, 347(9017):1713–27.
• 21. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet (London, England) 1997, 350(9084):1047–59.
• 22. Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE: Increased cell division as a cause of human cancer. Cancer Res 1990, 50(23):7415–21.
• 23. Yue, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL: Genotoxic metabolites of estradiol in breast: Potential mechanism of estradiol induced carcinogenesis. J Steroid Biochem Mol Biol 2003, 86(3–5):477–86.
• 24. Kumar V, Chambon P: The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell 1988, 55(1):145–56.
• 25. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC: Production and actions of estrogens. N Engl J Med 2002, 346(5):340–52.
• 26. Hall JM, McDonnell DP: Coregulators in Nuclear Estrogen Receptor Action: From Concept to Therapeutic Targeting. Mol Interv 2005, 5(6):343–57.
• 27. Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T: Catechol estrogen quinones as initiators of breast and other human cancers: Implications for biomarkers of susceptibility and cancer prevention. Biochimica et Biophysica Acta - Reviews on Cancer 2006, 1766: 63–78.
• 28. Cavalieri EL, Rogan EG: Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. Journal of Steroid Biochemistry and Molecular Biology 2011, 125: 169–80.
• 29. Rogan EG, Badawi AF, Devanesan PD, Meza JL, Edney JA, West WW, Higginbotham SM, Cavalieri EL: Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: potential biomarkers of susceptibility to cancer. Carcinogenesis 2003, 24(4):697–702.
• 30. Cavalieri EL, Rogan EG: The etiology and prevention of breast cancer. Drug Discovery Today: Disease Mechanisms 2012, 9: e55–69.
• 31. Cavalieri E, Rogan E: The molecular etiology and prevention of estrogen-initiated cancers: Ockham’s Razor: Pluralitas non est ponenda sine necessitate. Plurality should not be posited without necessity. Mol Aspects Med 2014, 36(1):1–55.
• 32. Liehr JG. Breast canrcinogenesis and itsprevention bt inhibition of estrogen genotoxicity. In: Endocrine Therapy in Breast Cancer. Marcel Dekker Inc: New York ,USA. 2002: pp 1–18.
• 33. Yager JD: Mechanisms of estrogen carcinogenesis: The role of E2/E1-quinone metabolites suggests new approaches to preventive intervention - A review. Steroids 2015, 99(Pt A): 56–60.
• 34. Singh S, Chakravarti D, Edney JA, Hollins RR, Johnson PJ, West WW, Higginbotham SM, Cavalieri EL, Rogan EG: Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. Oncol Rep 2005, 14(4):1091–6.
• 35. Yang L, Zahid M, Liao Y, Rogan EG, Cavalieri EL, Davidson NE, Yager JD, Visvanathan K, Groopman JD, Kensler TW: Reduced formation of depurinating estrogen-DNA adducts by sulforaphane or KEAP1 disruption in human mammary epithelial MCF-10A cells. Carcinogenesis 2013, 34(11):2587–92.
• 36. Zahid M, Gaikwad NW, Ali MF, Lu F, Saeed M, Yang L, Rogan EG, Cavalieri EL: Prevention of estrogen-DNA adduct formation in MCF-10F cells by resveratrol. Free Radic Biol Med 2008, 45(2):136–45.
• 37. Beatson GT: On the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases. Trans Medico-Chirurgical Soc Edinburgh 1896, 15:153–79.
• 38. Barker S: Anti-estrogens in the treatment of breast cancer: current status and future directions. Curr Opin Investig Drugs 2003, 4(6):652–7.
• 39. Wong ZW, Ellis MJ: First-line endocrine treatment of breast cancer: aromatase inhibitor or antioestrogen? Br J Cancer 2004, 90(1):20–5.
• 40. Oseni T, Patel R, Pyle J, Jordan V: Selective Estrogen Receptor Modulators and Phytoestrogens. Planta Med 2008, 74(13): 1656–65.
• 41. Nilsson S, Koehler KF: Oestrogen Receptors and Selective Oestrogen Receptor Modulators: Molecular and Cellular Pharmacology. Basic Clin Pharmacol Toxicol. 2005, 96(1):15–25.
• 42. McKenna NJ, Lanz RB, O’Malley BW: Nuclear Receptor Coregulators: Cellular and Molecular Biology. Endocr Rev 1999, 20(3):321–44.
• 43. Smith CL, Nawaz Z, O’Malley BW: Coactivator and Corepressor Regulation of the Agonist/Antagonist Activity of the Mixed Antiestrogen, 4-Hydroxytamoxifen. Mol Endocrinol 1997, 11(6):657–66.
• 44. Jordan VC: Tamoxifen: Catalyst for the change to targeted therapy. Eur. J. Cancer 2008, 44:30–8.
• 45. Shang Y, Brown M: Molecular determinants for the tissue specificity of SERMs. Science 2002, 295(5564):2465–8. 46. Riggs BL, Hartmann LC: Selective Estrogen-Receptor Modulators — Mechanisms of Action and Application to Clinical Practice. The new england journal of medicine 2003, 348(12):1–12.
• 47. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JGM, Sahmoud T, ATAC Trialists Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet (London, England) 2002, 359(9324):2131–9.
• 48. Assikis VJ, Neven P, Jordan VC, Vergote I: A realistic clinical perspective of tamoxifen and endometrial carcinogenesis. Eur J Cancer 1996, 32A(9):1464–76.
• 49. Black LJ, Jones CD, Falcone JF: Antagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci 1983, 32(9):1031–6.
• 50. Gottardis MM, Jordan VC: Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 1987, 47(15):4020–4.
• 51. Gottardis MM, Ricchio ME, Satyaswaroop PG, Jordan VC: Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res 1990, 50(11):3189–92. 52. Jordan VC, Phelps E, Lindgren JU: Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 1987, 10(1):31–5.
• 53. Wakeling AE: Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000, 7(1):17–28.
• 54. Howell A, Osborne CK, Morris C, Wakeling AE: ICI 182,780 (Faslodex): development of a novel, “pure” antiestrogen. Cancer 2000, 89(4):817–25.
• 55. Wakeling AE, Dukes M, Bowler J: A potent specific pure antiestrogen with clinical potential. Cancer Res 1991, 51(15):3867–73.
• 56. Wade GN, Blaustein JD, Gray JM, Meredith JM: ICI 182,780: a pure antiestrogen that affects behaviors and energy balance in rats without acting in the brain. Am J Physiol 1993, 265(6 Pt 2):R1392-8.
• 57. Robertson JF: Estrogen receptor downregulators: New antihormonal therapy for advanced breast cancer. Clin Ther 2002, 24 (SUPPL. A).
• 58. Miller WR: Endocrine treatment for breast cancers: biological rationale and current progress. J Steroid Biochem Mol Biol 1990, 37(4):467–80.
• 59. Pasqualini JR, Chetrite GS: Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol 2005, 93(2–5): 221–36.
• 60. Suzuki T, Miki Y, Nakata T, Shiotsu Y, Akinaga S, Inoue K, Ishida T, Kimura M, Moriya T, Sasano H: Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma. J Steroid Biochem Mol Biol 2003, 86(3–5):449–54.
• 61. Hilborn E, Stal O, Jansson A: Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer. Oncotarget 2017, 8(18).
• 62. Bulun S, Zeitoun K, Sasano H, Simpson E: Aromatase in Aging Women. Semin Reprod Med 1999, 17(04):349–58.
• 63. Simpson E, Rubin G, Clyne C, Robertson K, O’Donnell L, Davis S, Jones, M: Local estrogen biosynthesis in males and females. Endocr Relat Cancer. 1999, 6(2):131–7.
• 64. Berry J: Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. Clin Ther 2005, 27(11):1671–84.
• 65. Brueggemeier RW, Hackett JC, Diaz-Cruz ES: Aromatase inhibitors in the treatment of breast cancer. Endocr Rev 2005, 26(3):331–45.
• 66. Ghosh D, Lo J, Egbuta C: Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective. J Med Chem 2016, 59(11):5131–48.
• 67. Dizdar O, Ozçakar L, Malas FU, Harputluoglu H, Bulut N, Aksoy S, Ozisik Y, Altundag K: Sonographic and electrodiagnostic evaluations in patients with aromatase inhibitor-related arthralgia. J Clin Oncol 2009, 27(30):4955–60.
• 68. Tomao F, Spinelli G, Vici P, Pisanelli GC, Cascialli G, Frati L, Panici PB, Tomao S: Current role and safety profile of aromatase inhibitors in early breast cancer. Expert Rev Anticancer Ther 2011, 11(8):1253–63.
• 69. Jansen MPHM, Knijnenburg T, Reijm EA, Simon I, Kerkhoven R, Droog M, Velds A, van Laere S, Dirix L, Alexi X, Foekens JA, Wessels L, Linn SC, Berns EMJJ, Zwart W: Hallmarks of aromatase inhibitor drug resistance revealed by epigenetic profiling in breast cancer. Cancer Res 2013, 73(22):6632–41.
• 70. Prior AM, Yu X, Park EJ, Kondratyuk TP, Lin Y, Pezzuto JM, Sun D: Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1. Bioorganic Med Chem Lett 2017, 27(24):5393–9.
• 71. González-González A, Mediavilla MD, Sánchez-Barceló EJ: Melatonin: A Molecule for Reducing Breast Cancer Risk. Molecules 2018, 23(2):336.
• 72. Jordan C, Furr BJA. An Introduction to the Regulation of Sex Steroids for the Treatment of Cancer. In: HormoneTherapy in Breast and Prostate Cancer. Humana Press; 2006: pp 1–16.
• 73. Johnston JO: Aromatase inhibitors. Crit Rev Biochem Mol Biol 1998, 33(5):375–405.
• 74. Kao YC, Cam LL, Laughton CA, Zhou D, Chen S: Binding characteristics of seven inhibitors of human aromatase: a site-directed mutagenesis study. Cancer Res 1996, 56(15):3451–60.
• 75. Vanden Bossche HV, Moereels H, Koymans LM: Aromatase inhibitors--mechanisms for non-steroidal inhibitors. Breast Cancer Res Treat 1994, 30(1):43–55.
• 76. Santen RJ, Misbin RI: Aminoglutethimide: review of pharmacology and clinical use. Pharmacotherapy 1981, 1(2):95–120.
• 77. Lipton A, Santen RJ: Proceedings: Medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer 1974, 33(2):503–12.
• 78. Hughss SW, Burley DM: Aminoglutethimide: a vequot;side-effectvequot; turned to therapeutic advantage. Postgraduate Medical Journal 1970, 46(537):409–16.
• 79. Lonning PE: Aromatase inhibition for breast cancer treatment. Acta Oncol 1996, 35 Suppl 5:38–43.
• 80. Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE: In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1995, 1(12):1511–5.
• 81. Demers LM: Effects of Fadrozole (CGS 16949A) and Letrozole (CGS 20267) on the inhibition of aromatase activity in breast cancer patients. Breast Cancer Res Treat 1994, 30(1):95–102.
• 82. Evans TR, Di Salle E, Ornati G, Lassus M, Benedetti MS, Pianezzola E, Coombes RC: Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res 1992, 52(21):5933–9. 83. Hammond DK, Zhu BT, Wang MY, Ricci MJ, Liehr JG: Cytochrome P450 metabolism of estradiol in hamster liver and kidney. Toxicol Appl Pharmacol 1997, 145(1):54–60.
• 84. Raftogianis R, Creveling C, Weinshilboum R, Weisz J: Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr 2000, (27):113–24.
• 85. Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR: 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci U S A 1996, 93(18):9776–81.
• 86. Gajjar K, Martin-Hirsch PL, Martin FL: CYP1B1 and hormone-induced cancer. Cancer Lett 2012, 324(1):13–30.
• 87. Chun YJ, Kim S: Discovery of Cytochrome P450 1B1 Inhibitors as New Promising Anti-Cancer Agents. Med Res Rev 2003, 23(6):657–68.
• 88. Bruno RD, Njar VCO: Targeting cytochrome P450 enzymes: a new approach in anti-cancer drug development. Bioorg Med Chem 2007, 15(15):5047–60.
• 89. Zheng W, Xie DW, Jin F, Cheng JR, Dai Q, Wen WQ, Shu XO, Gao YT: Genetic polymorphism of cytochrome P450-1B1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2000, 9(2):147–50.
• 90. Cuendet M, Oteham CP, Moon RC, Pezzuto JM: Quinone reductase induction as a biomarker for cancer chemoprevention. J Nat Prod 2006, 69(3):460–3.
• 91. Lavigne JA, Goodman JE, Fonong T, Odwin S, He P, Roberts DW, Yager JD: The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. Cancer Res 2001, 61(20):7488–94.
• 92. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, et al. Multifactor-Dimensionality Reduction Reveals High-Order Interactions among Estrogen-Metabolism Genes in Sporadic Breast Cancer. Am J Hum Genet. 2001, 69(1):138–47.
• 93. Acuña Castroviejo D, López LC, Escames G, López A, García JA, Reiter RJ: Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 2011, 11:221–40.
• 94. Sanchez-Barcelo EJ, Martinez-Campa CM, Mediavilla MD, Gonzalez A, Alonso-Gonzalez C, Cos S: Melatonin and Melatoninergic Drugs as Therapeutic Agents: Ramelteon and Agomelatine, the Two Most Promising Melatonin Receptor Agonists. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2007, 1: 142–51.
• 95. Karasek M, Winczyk K: Melatonin in humans. J Physiol Pharmacol 2006, 57 Suppl 5:19–39.
• 96. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z: Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 2003, 50(4):1129–46.
• 97. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S: Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci 2007, 52:11–28.
• 98. Cos S, González A, Martínez-Campa C, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ: Melatonin as a selective estrogen enzyme modulator. Curr Cancer Drug Targets 2008, 8(8):691–702.
• 99. Sánchez-Barceló EJ, Cos S, Mediavilla D, Martínez-Campa C, González A, Alonso-González C: Melatonin-estrogen interactions in breast cancer. J Pineal Res 2005, 38(4):217–22.
• 100. Davis S, Mirick DK, Stevens RG: Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 2001, 93(20):1557–62.
• 101. Hansen J: Increased breast cancer risk among women who work predominantly at night. Epidemiology 2001, 12(1):74–7.
• 102. Reiter RJ, Tan DX, Erren TC, Fuentes-Broto L, Paredes SD: Light-mediated perturbations of circadian timing and cancer risk: a mechanistic analysis. Integr Cancer Ther 2009, 8(4):354–60.
• 103. Cos S, Sánchez-Barceló EJ: Melatonin and mammary pathological growth. Front Neuroendocrinol 2000, 21(2):133–70.
• 104. Hill SM, Blask DE: Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 1988, 48(21):6121–6.
• 105. Sánchez-Barceló EJ, Cos S, Fernández R, Mediavilla MD: Melatonin and mammary cancer: a short review. Endocr Relat Cancer 2003, 10(2):153–9.
• 106. Cos S, Fernández R, Güézmes A, Sánchez-Barceló EJ: Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res 1998, 58(19):4383–90.
• 107. Mediavilla MD, Güezmez A, Ramos S, Kothari L, Garijo F, Sánchez Barceló EJ: Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene. J Pineal Res 1997, 22(2):86–94.
• 108. Molis TM, Spriggs LL, Jupiter Y, Hill SM: Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer. J Pineal Res 1995, 18(2):93–103.
• 109. Wilson ST, Blask DE, Lemus-Wilson AM: Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro. J Clin Endocrinol Metab 1992, 75(2):669–70.
• 110. Molis T, Walters M, Hill S: Melatonin modulation of estrogen-receptor expression in mcf-7 human breast-cancer cells. Int J Oncol 1993, 3(4):687–94.
• 111. Molis TM, Spriggs LL, Hill SM: Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. Mol Endocrinol 1994, 8(12):1681–90.
• 112. Rato AG, Pedrero JG, Martinez MA, del Rio B, Lazo PS, Ramos S: Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J 1999, 13(8):857–68.
• 113. Yuan L, Collins AR, Dai J, Dubocovich ML, Hill SM: MT1 melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells. Mol Cell Endocrinol 2002, 192(1–2):147–56.
• 114. Lai L, Yuan L, Chen Q, Dong C, Mao L, Rowan B, Frasch T, Hill SM: The Galphai and Galphaq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation. J Pineal Res 2008, 45(4):476–88.
• 115. Cos S, González A, Martínez-Campa C, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ: Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev 2006, 30(2):118–28.
• 116. Chang TKH, Chen J, Yang G, Yeung EYH: Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin. J Pineal Res 2010, 48(1):55–64.
• 117. Lissoni P, Barni S, Cattaneo G, Tancini G, Esposti G, Esposti D, Fraschini F: Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991, 48(6):448–50.
• 118. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G: A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994, 73(3):699–701.
• 119. Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, Tancini G: 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 1995, 71(4):854–6.
• 120. Panzer A, Viljoen M: The validity of melatonin as an oncostatic agent. J Pineal Res 1997, 22(4):184–202.
• 121. Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ: Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs 2012, 21(6):819–31.
• 122. Shirazi A, Mihandoost E, Mohseni M, Ghazi-Khansari M, Rabie Mahdavi S: Radio-protective effects of melatonin against irradiation-induced oxidative damage in rat peripheral blood. Phys Medica 2013, 29(1):65–74.