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Licensed Unlicensed Requires Authentication Published by De Gruyter January 12, 2019

Melatonin and its anti-glioma functions: a comprehensive review

Sayantan Maitra, Debanjan Bhattacharya, Stabak Das and Subhrajit Bhattacharya ORCID logo


Melatonin (N-acetyl-5-methoxytryptamine) is a naturally synthesized hormone secreted from the pineal gland in a variety of animals and is primarily involved in the regulation of the circadian rhythm, which is the natural cycle controlling sleep in organisms. Melatonin acts on specific receptors and has an important role in overall energy metabolism. This review encompasses several aspects of melatonin activity, such as synthesis, source, structure, distribution, function, signaling and its role in normal physiology. The review highlights the cellular signaling and messenger systems involved in melatonin’s action on the body and their wider implications, the distribution and diverse action of different melatonin receptors in specific areas of the brain, and the pharmacological agonists and antagonists that have specific action on these melatonin receptors. This review also incorporates the antitumor effects of melatonin in considerable detail, emphasizing on melatonin’s role as an adjuvant therapeutic agent in glioma treatment. We conclude that the diminishing levels of melatonin have significant debilitating effects on normal physiology and can also be associated with malignant conditions such as glioma. Based on the review of the available evidence, our study provides a broad platform for a better understanding of the specific roles of melatonin and serves as a starting point for further investigation into the therapeutic effect of melatonin in glioma as an adjuvant therapeutic agent.


Arendt, J. (1995). Melatonin and the Mammalian Pineal Gland. (London: Chapman & Hall), pp. 1–331.Search in Google Scholar

Armstrong, S.M. (1989). Melatonin: the internal zeitgeber of mammals. Pineal Res. 7, 157–202.Search in Google Scholar

Axelrod, J. (1974). The pineal gland: a neurochemical transducer. Science 1184, 1341–1348.10.1126/science.184.4144.1341Search in Google Scholar

Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., Hjelmeland, A.B., Dewhirst, M.W., Bigner, D.D., Rich, J.N. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760.10.1038/nature05236Search in Google Scholar PubMed

Beier, D., Schulz, J.B., and Beier, C.P. (2011). Chemoresistance of glioblastoma cancer stem cells – much more complex than expected. Mol. Cancer 10, 128.10.1186/1476-4598-10-128Search in Google Scholar PubMed

Bertuglia, S., Marchiafa, P.L., and Colantuoni, A. (1996). Melatonin prevents ischemia reperfusion injury in the hamster cheek pouch. Cardiovasc. Res. 31, 947–952.10.1016/S0008-6363(96)00030-2Search in Google Scholar PubMed

Blask, D.E., Sauer, L.A., and Dauchy, R.T. (2002). 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, 113–132.10.2174/1568026023394407Search in Google Scholar PubMed

Brat, D.J., Verhaak, R.G., Aldape, K.D., Yung, W.K., Salama, S.R., Cooper, L.A., Rheinbay, E., Miller, C.R., Vitucci, M., Morozova, O., et al. (2015). Cancer genome atlas research network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498.10.1056/NEJMoa1402121Search in Google Scholar PubMed PubMed Central

Bravo, R., Matito, S., Cubero, J., Paredes, S.D., Franco, L., Rivero, M., Rodríguez, A.B., and Barriga, C. (2013). Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. Age (Dordr.) 35, 1277–1285.10.1007/s11357-012-9419-5Search in Google Scholar PubMed PubMed Central

Bubenik, G.A. (2002). Gastrointestinal melatonin: localization, function and clinical relevance. Dig Dis Sci. 47, 2336–2348.10.1023/A:1020107915919Search in Google Scholar PubMed

Buscemi, N., Vandermeer, B., Hooton, N., Pandya, R., Tjosvold, L., Hartling, L., Vohra, S., Klassen, T.P., and Baker, G. (2006). Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. Br. Med. J. 332, 385–393.10.1136/bmj.38731.532766.F6Search in Google Scholar PubMed PubMed Central

Cagnacci, A. (1996). Melatonin in relation to physiology in adult humans. J. Pineal Res. 21, 200–213.10.1111/j.1600-079X.1996.tb00287.xSearch in Google Scholar PubMed

Cardinali, D.P. and Pevet, P. (1998). Basic aspects of melatonin action. Sleep Med Rev 3, 175–190.10.1016/S1087-0792(98)90020-XSearch in Google Scholar

Carlberg, C. (2000). Gene regulation by melatonin. Ann NY Acad Sci 917, 387–396.10.1111/j.1749-6632.2000.tb05403.xSearch in Google Scholar

Carrillo-Vico, A., Garica-Maurino, S., Calvo, S.J., and Guerrero, J.M. (2003). Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. FASEB J. 17, 755–757.10.1096/fj.02-0501fjeSearch in Google Scholar PubMed

Carrillo-Vico, A., Clavo, J.R., Abreu, P., Lardone, P.J., Garcia-Maurino, S., Reiter, R.J., and Guerrero, J.M. (2004). Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 18, 537–539.10.1096/fj.03-0694fjeSearch in Google Scholar PubMed

Chan, A.S., Lai, F.P., Lo, R.K., Voyno-Yasenetskaya, T.A., Stanbridge, E.J., and Wong, Y.H. (2002). Melatonin MT1 and MT2 receptors stimulate c-Jun N-terminal kinase via pertussis toxinsensitive and -insensitive G proteins. Cell Signal 14, 249–257.10.1016/S0898-6568(01)00240-6Search in Google Scholar

Chen, G., Huo, Y., Tan, D.X., Liang, Z., Zhang, W., and Zhang, Y. (2003). Melatonin in Chinese medicinal herbs. Life Sci. 73, 19–26.10.1016/S0024-3205(03)00252-2Search in Google Scholar PubMed

Chen, J., Li, Y., Yu, T.S., McKay, R.M., Burns, D.K., Kernie, S.G., and Parada, L.F. (2012). A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526.10.1038/nature11287Search in Google Scholar PubMed PubMed Central

Chen, B., Liu, J., Chang, Q., Beezhold, K., Lu, Y., and Chen, F. (2013). JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic. Cell Cycle 12, 112–121.10.4161/cc.23030Search in Google Scholar PubMed PubMed Central

Chen, X., Hao, A., Li, X., Du, Z., Li, H., Wang, H., Yang, H., and Fang, Z. (2016). Melatonin inhibits tumorigenicity of glioblastoma stem-like cells via the AKT-EZH2-STAT3 signaling axis. J. Pineal Res. 612, 208–217.10.1111/jpi.12341Search in Google Scholar PubMed

Chen, D., Li, Y.P., Yu, Y.X., Zhou, T., Liu, C., Fei, E.K., Gao, F., Mu, C.C., Ren, H.G., and Wang, G.H. (2018). Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells. Acta Pharmacol. Sin. 39, 597–606.10.1038/aps.2017.163Search in Google Scholar PubMed PubMed Central

Chowdhury, I., Sengupta, A., and Maitra, SK. (2008). Melatonin: fifty years of scientific journey from the discovery in Bovine pineal gland to Delineation of functions in human. Ind. J. Biochem. Biophys. 45, 289–304.Search in Google Scholar

Claustrat, B., Brun, J., and Chazot, G. (2005). The basic physiology and pathophysiology of melatonin. Sleep Med. Rev. 9, 11–24.10.1016/j.smrv.2004.08.001Search in Google Scholar PubMed

Cohen, M., Lippman, M., and Chabner, B. (1978). Role of pineal gland in aetiology and treatment of breast cancer. Lancet 2, 814–816.10.1016/S0140-6736(78)92591-6Search in Google Scholar PubMed

Colombo, J., Maciel, J.M., Ferreira, L.C., Da Silva, R.F., and Zuccari, D.A. (2016). Effects of melatonin on HIF-1α and VEGF expression and on the invasive properties of hepatocarcinoma cells. Oncol. Lett. 12, 231–237.10.3892/ol.2016.4605Search in Google Scholar PubMed

Conti, A., Conconi, S., Hertens, E., Skwarlo-Sonta, K., Markowska, M., and Maestroni, G.J.M. (2000). Evidence for melatonin synthesis in mouse and human bone marrow cells. J. Pineal Res. 28, 193–202.10.1034/j.1600-079X.2000.280401.xSearch in Google Scholar PubMed

Cutando, A., López-Valverde, A., Arias-Santiago, S., De Vicente, J., and De Diego, R.G. (2012). Role of melatonin in cancer treatment. Anticancer Res. 32, 2747–2753.Search in Google Scholar PubMed

Cuzzocrea, S. and Reiter, R.J. (2002). Pharmacological actions of melatonin in acute and chronic inflammation. Curr. Top Med. Chem 2, 153–165.10.2174/1568026023394425Search in Google Scholar PubMed

Cuzzocrea, S., Costantino, G., Mazzon, E., and Caputi, A.P. (1999). Regulation of prostaglandin production in carrageenan-induced pleurisy by melatonin. J. Pineal Res. 27, 9–14.10.1111/j.1600-079X.1999.tb00591.xSearch in Google Scholar PubMed

Cuzzocrea, S., Misko, T.P., Costantino, G., Mazzon, E., Micali, A., Caputi, A.P., Macarthur, H., and Salvemini, D. (2000). Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion. FASEB J. 14, 1061–1072.10.1096/fasebj.14.9.1061Search in Google Scholar

El-Shenawy, S.M., Abdel-Salam, O.M., Baiuomy, A.R., El-Batran, S., and Arbid, M.S. (2002). Studies on the anti-inflammatory and antinociceptive effects of melatonin in the rat. Pharmacol Res. 46, 235–243.10.1016/S1043-6618(02)00094-4Search in Google Scholar

Galano, A., Tan, D.X., and Reiter, R.J. (2011). Melatonin as a natural ally against oxidative stress: a physicochemical examination. J. Pineal Res. 51, 1–16.10.1111/j.1600-079X.2011.00916.xSearch in Google Scholar PubMed

Galli, R., Binda, E., Orfanelli, U., Cipelletti, B., Gritti, A., De Vitis, S., Fiocco, R., Foroni, C., Dimeco, F., and Vescovi, A. (2004). Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021.10.1158/0008-5472.CAN-04-1364Search in Google Scholar PubMed

Ghosh, A.K., Naaz, S., Bhattacharjee, B., Ghosal, N., Chattopadhyay, A., Roy, S., Reiter, R.J., and Bandyopadhyay, D. (2017). Mechanism of melatonin protection against copper-ascorbate-induced oxidative damage in vitro through isothermal titration calorimetry. Life Sci. 180, 123–136.10.1016/j.lfs.2017.05.022Search in Google Scholar PubMed

Godson, C. and Reppert, S.M. (1997). The Mel1a melatonin receptor is coupled to parallel signal transduction pathways. Endocrinology 138, 397–404.10.1210/endo.138.1.4824Search in Google Scholar PubMed

Habtemariam, S., Daglia, M., Sureda, A., Selamoglu, Z., Gulhan, M.F., and Nabavi, S.M. (2017). Melatonin and respiratory diseases: a review. Curr. Top Med. Chem. 17, 467–488.10.2174/1568026616666160824120338Search in Google Scholar PubMed

Hardeland, R., Cardinali, D.P., Srinivasan, V., Spence, D.W., Brown, G.M., and Pandi-Perumal, S.R. (2011). Melatonin – a pleiotropic, orchestrating regulator molecule. Prog. Neurobiol. 93, 350–384.10.1016/j.pneurobio.2010.12.004Search in Google Scholar PubMed

Hardeland, R. and Poeggeler, B. (2003). Non-vertebrate melatonin. J. Pineal Res. 34, 233–241.10.1034/j.1600-079X.2003.00040.xSearch in Google Scholar PubMed

Hardeland, R. and Pandi-Perumal, S.R. (2005). Melatonin, a potent agent in antioxidative defense: actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr. Metab. Lond. 2, 22.10.1186/1743-7075-2-22Search in Google Scholar PubMed

He, C., Wang, J., Zhang, Z., Yang, M., Li, Y., Tian, X., Ma, T., Tao, J., Zhu, K., Song, Y., et al. (2016). Mitochondria synthesize melatonin to ameliorate its function and improve mice oocyte’s quality under in vitro conditions. Int. J. Mol. Sci. 17, pii: E939.10.3390/ijms17060939Search in Google Scholar

Hickman, A.B., Klein, D.C., and Dyda, F. (1999). Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 Å resolution suggests a catalytic mechanism. Mol. Cell 3, 23–32.10.1016/S1097-2765(00)80171-9Search in Google Scholar PubMed

Ikegami, T., Azuma, K., Nakamura, M., Suzuki, N., Hattori, A., and Ando, H. (2009). Diurnal expressions of four subtypes of melatonin receptor genes in the optic tectum and retina of goldfish. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 152, 219–224.10.1016/j.cbpa.2008.09.030Search in Google Scholar PubMed

Ishii, H., Tanaka, N., Kobayashi, M., Kato, M., and Sakuma, Y. (2009). Gene structures, biochemical characterization and distribution of rat melatonin receptors. J. Physiol. Sci. 59, 37–47.10.1007/s12576-008-0003-9Search in Google Scholar PubMed

Jung, B. and Ahmad, N (2006). Melatonin in cancer management progress and promise. Cancer Res. 66, 9789–9793.10.1158/0008-5472.CAN-06-1776Search in Google Scholar PubMed

Karasek, M. (2006). Melatonin in Human Physiology and Pathology. Frontiers in Chronobiology Research. F. Columbus, ed. (NY, USA: Nova Science/Hauppage), pp. 1–43.Search in Google Scholar

Karasek, M. and Winczyk, K. (2006). Melatonin in humans. J. Physiol. Pharmacol. 57, 19–39.Search in Google Scholar PubMed

Kim, E., Kim, M., Woo, D.H., Shin, Y., Shin, J., Chang, N., Oh, Y.T., Kim, H., Rheey, J., Nakano, I., et al. (2013). Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839–852.10.1016/j.ccr.2013.04.008Search in Google Scholar PubMed

Klein, D.C. and Moore, R.Y. (1979). Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus. Brain Res. 174, 245–262.10.1016/0006-8993(79)90848-5Search in Google Scholar PubMed

Konopka, G. and Bonni, A. (2003). Signaling pathways regulating gliomagenesis. Curr. Mol. Med. 31, 73–84.10.2174/1566524033361609Search in Google Scholar

Lee, H.Y., Byeon, Y., Lee, K., Lee, H.J., and Back, K. (2014). Cloning of Arabidopsis serotonin N-acetyltransferase and its role with caffeic acid O-methyltransferase in the biosynthesis of melatonin in vitro despite their different subcellular localizations. J. Pineal Res. 57, 418–426.10.1111/jpi.12181Search in Google Scholar PubMed

Lerner, A.B., Case, J.D., Takahashi, Y., Lee, F., and Mori, W. (1958). Isolation of melatonin, the pineal factor that lightens melanocytes. J. Am. Chem. Soc. 8, 2587.10.1021/ja01543a060Search in Google Scholar

Lissoni, P., Barni, S., Ardizzoia, A., Tancini, G., Conti, A., and Maestroni, G. (1994). A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 73, 699–701.10.1002/1097-0142(19940201)73:3<699::AID-CNCR2820730332>3.0.CO;2-LSearch in Google Scholar PubMed

Liu, C., Fukuhara, C., Wessel III, J.H., Iuvone, P.M., and Tosini, G. (2004). Localization of Aanat mRNA in the rat retina by fluorescence in situ hybridization and laser capture microdissection. Cell Tissue Res. 315, 197–201.10.1007/s00441-003-0822-1Search in Google Scholar

Louis, D.N., Ohgaki, H., Wiestler, O.D., and Cavenee, W.K. (2016). WHO Classification of Tumours of the Central Nervous System, Revised 4th ed. (Lyon, France: International Agency for Research on Cancer (IARC)), pp. 10–122.Search in Google Scholar

Luchetti, F., Betti, M., Canonico, B., Arcangeletti, M., Ferri, P., Galli, F., and Papa, S. (2009). ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells. Free Radic. Biol. Med. 46, 339–351.10.1016/j.freeradbiomed.2008.09.017Search in Google Scholar PubMed

Martin, X.D., Malina, H.Z., Brennan, M.C., Hendrikson, P.H., and Lichter, P.R. (1992). The ciliary body-the third organ found to synthesize idoleamines in humans. Eur. J. Ophthalmol. 2, 67–72.10.1177/112067219200200203Search in Google Scholar

Martin, M., Macias, M., Escames, G., Leon, J., and Acuna-Castroviejo, D. (2000). Melatonin but not vitamins C and E maintains glutathione homeostasis in tert-butyl hydroperoxide-induced mitochondrial oxidative stress. FASEB J. 14, 1677–1679.10.1096/fj.99-0865fjeSearch in Google Scholar PubMed

Martin, V., Herrera, F., Carrera-Gonzalez, P., García-Santos, G., Antolín, I., Rodriguez-Blanco, J., and Rodriguez, C. (2006). Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res. 66, 1081–1088.10.1158/0008-5472.CAN-05-2354Search in Google Scholar PubMed

Martín, V., García-Santos, G., Rodriguez-Blanco, J., Casado-Zapico, S., Sanchez-Sanchez, A., Antolín, I., and Rodriguez, C. (2010) Melatonin sensitizes human malignant glioma cells against TRAIL-induced cell death. Cancer Lett. 287, 216–223.10.1016/j.canlet.2009.06.016Search in Google Scholar PubMed

Martín, V., Sanchez-Sanchez, A.M., Herrera, F., Gomez-Manzano, C., Fueyo, J., Alvarez-Vega, M.A., Antolín, I., and Rodriguez, C. (2013). Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells. Br. J. Cancer 10810, 2005–2012.10.1038/bjc.2013.188Search in Google Scholar PubMed PubMed Central

Martín-Renedo, J., Mauriz, J.L., Jorquera, F., Ruiz-Andrés, O., González, P., and González-Gallego, J. (2008). Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J. Pineal Res. 45, 532–540.10.1111/j.1600-079X.2008.00641.xSearch in Google Scholar PubMed

Mauriz, J.L., Collado, P.S., Veneroso, C., Reiter, R.J., and González-Gallego, J. (2013). A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J. Pineal Res. 54, 1–14.10.1111/j.1600-079X.2012.01014.xSearch in Google Scholar PubMed

Mayo, J.C., Sainz, R.M., Tan, D.X., Hardeland, R., Leon, J., Rodriguez, C., and Reiter, R.J. (2005). Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J. Neuroimmunol. 165, 139–149.10.1016/j.jneuroim.2005.05.002Search in Google Scholar PubMed

Mediavilla, M.D., Sánchez-Barceló, E.J., Tan, D.X., Manchester, L., and Reiter, R.J. (2010). Basic mechanisms involved in the anti-cancer effects of melatonin. Curr. Med. Chem. 36, 4462–4480.10.2174/092986710794183015Search in Google Scholar PubMed

Meng, X., Li, Y., Li, S., Zhou, Y., Gan, R.Y., Xu, D.P., and Li, H.B. (2017). Dietary sources and bioactivities of melatonin. Nutrients 9, pii: E367.10.3390/nu9040367Search in Google Scholar PubMed PubMed Central

Morin, D., Simon, N., Depres-Brummer, P., Lévi, F., Tillement, J.P., and Urien, S. (1997). Melatonin high affinity binding to alpha-1-acid glycoprotein in human serum. Pharmacology 54, 271–275.10.1159/000139495Search in Google Scholar PubMed

Nosjean, O., Ferro, M., Coge, F., Beauverger, P., Henlin, J.M., Lefoulon, F., Fauchere, J.L., Delagrange, P., Canet, E., and Boutin, J.A. (2000). Identification of the melatonin-binding site MT3 as the quinone reductase 2. J. Biol. Chem. 275, 31311–31317.10.1074/jbc.M005141200Search in Google Scholar PubMed

Pandi-Perumal, S.R., Srinivasan, V., Maestoni, G.J.M., Cardinali, D.P., Poeggeler, B., and Hardeland, R. (2006). Melatonin: nature’s most versatile signal? FEBS J. 273, 2813–2838.10.1111/j.1742-4658.2006.05322.xSearch in Google Scholar PubMed

Pardridge, W.M. and Mietus, L.J. (1980). Transport of albumin-bound melatonin through the blood–brain barrier. J. Neurochem. 34, 1761–1763.10.1111/j.1471-4159.1980.tb11272.xSearch in Google Scholar PubMed

Paredes, S.D., Korkmaz, A., and Manchester, L.C. (2004). Macchia MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front. Neuroendocrinol. 25, 177–195.10.1016/j.yfrne.2004.08.001Search in Google Scholar PubMed

Park, H.J., Kim, H.J., Ra, J., Hong, S.J., Baik, H.H., Park, H.K., Yim, S.V., Nah, S.S., Cho, J.J., and Chung, J.H. (2007). Melatonin inhibits lipopolysaccharide-induced CC chemokine subfamily gene expression in human peripheral blood mononuclear cells in a microarray analysis. J. Pineal Res. 43, 121–129.10.1111/j.1600-079X.2007.00452.xSearch in Google Scholar PubMed

Pearson, J.R.D. and Regad, T. (2017). Targeting cellular pathways in glioblastoma multiforme. Signal Transduct. Targeted Ther. 2, 17040.10.1038/sigtrans.2017.40Search in Google Scholar PubMed PubMed Central

Reiter, R.J. (1981). The mammalian pineal gland: structure and function. Am. J. Anat. 162, 287–313.10.1002/aja.1001620402Search in Google Scholar PubMed

Reiter, R.J. (1991). Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr. Rev. 12, 151–180.10.1210/edrv-12-2-151Search in Google Scholar PubMed

Reiter, R.J. and Tan, D.X. (2002). Melatonin: an antioxidant in edible plants. Ann. NY Acad. Sci. 957, 341–344.10.1111/j.1749-6632.2002.tb02938.xSearch in Google Scholar PubMed

Reiter, R.J., Calvo, J.R., Karbownik, M., Qi, W., and Tan, D.X. (2000a). Melatonin and its relation to the immune system and inflammation. Ann. NY Acad. Sci. 917, 376–386.10.1111/j.1749-6632.2000.tb05402.xSearch in Google Scholar PubMed

Reiter, R.J., Tan, D.X., Osuna, C., and Gitto, E. (2000b). Actions of melatonin in the reduction of oxidative stress. A review. J. Biomed. Sci. 7, 444–458.10.1007/BF02253360Search in Google Scholar PubMed

Reiter, R.J., Tan, D.X., Burkhardt, S., and Manchester, L.C. (2001). Melatonin in plants. Nutr. Rev. 59, 286–290.10.1111/j.1753-4887.2001.tb07018.xSearch in Google Scholar PubMed

Reiter, R.J., Rosales-Corral, S.A., Manchester, L.C., and Tan, D.X. (2013). Peripheral reproductive organ health and melatonin: ready for prime time. Int. J. Mol. Sci. 14, 7231–7272.10.3390/ijms14047231Search in Google Scholar PubMed PubMed Central

Reiter, R.J., Mayo, J.C., Tan, D.X., Sainz, R.M., Alatorre-Jimenez, M., and Qin, L. (2016). Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res. 61, 253–278.10.1111/jpi.12360Search in Google Scholar PubMed

Reuss, D.E., Sahm, F., Schrimpf, D., Wiestler, B., Capper, D., Koelsche, C., Schweizer, L., Korshunov, A., Jones, DT., Hovestadt, V., et al. (2015). ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol. 129, 133–146.10.1007/s00401-014-1370-3Search in Google Scholar PubMed

Rondanelli, M., Faliva, M.A., Perna, S., and Antoniello, N. (2013). Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep–wake and mood disturbances: review and remarks. Aging Clin. Exp. Res. 25, 499–510.10.1007/s40520-013-0118-6Search in Google Scholar PubMed PubMed Central

Sahm, F., Reuss, D., Koelsche, C., Capper, D., Schittenhelm, J., Heim, S., Jones, D.T., Pfister, S.M., Herold-Mende, C., Wick, W., et al. (2014). Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 128, 551–559.10.1007/s00401-014-1326-7Search in Google Scholar PubMed

Sherry, M.M., Reeves, A., Wu, J.K., and Cochran, B.H. (2009). STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem. Cells 2710, 2383–2392.10.1002/stem.185Search in Google Scholar PubMed PubMed Central

Sidaway, P. (2017). CNS cancer: glioblastoma subtypes revisited. Nat. Rev. Clin. Oncol. 14, 587.10.1038/nrclinonc.2017.122Search in Google Scholar PubMed

Slominiski, A., Wortsman, J., and Tobin, D.J. (2005). The cutaneous serotonergic/melatonergic system; securing a place under the sun. FASEB J. 19, 176–194.10.1096/fj.04-2079revSearch in Google Scholar PubMed

Srinivasan, V., Cardinali, D.P., Pandi-Perumal, S.R., and Brown, G.M. (2011). Melatonin agonists for treatment of sleep and depressive disorders. Journal of Experimental and Integrative Medicine. 13, 149–158.10.5455/ in Google Scholar

Suva, M.L., Riggi, N., Janiszewska, M., Radovanovic, I., Provero, P., Stehle, J.C., Baumer, K., Le Bitoux, M.A., Marino, D., Cironi, L., et al. (2009). EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 69, 9211–9218.10.1158/0008-5472.CAN-09-1622Search in Google Scholar PubMed

Tamura, H., Takasaki, A., Taketani, T., Tanabe, M., Kizuka, F., Lee, L., Tamura, I., Maekawa, R., Aasada, H., Yamagata, Y., et al. (2012). The role of melatonin as an antioxidant in the follicle. J. Ovarian Res. 5, 5.10.1186/1757-2215-5-5Search in Google Scholar PubMed

Tan, D.X., Manchester, L.C., Terron, M.P., Flores, L.J., Tamura, H., and Reiter, R.J. (2007). Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT3 melatonin membrane receptor: hypothesis and significance. J. Pineal Res. 43, 317–320.10.1111/j.1600-079X.2007.00513.xSearch in Google Scholar PubMed

Tan, D.X., Hardeland, R., Manchester, L.C., Korkmaz, A., Ma, S., Rosales-Corral, S., and Reiter, R.J. (2012). Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. J. Exp. Bot. 63, 577–597.10.1093/jxb/err256Search in Google Scholar PubMed

Tan, D.X., Manchester, L.C., Esteban-Zubero, E., Zhou, Z., and Reiter, R.J. (2015). Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism. Molecules 20, 18886–18906.10.3390/molecules201018886Search in Google Scholar PubMed

Tan, D.X., Manchester, L.C., Qin, L, and Reiter, R.J. (2016). Melatonin: a mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int. J. Mol. Sci. 17, pii: E2124.10.3390/ijms17122124Search in Google Scholar

Tanaka, T., Yasui, Y., Tanaka, M., Tanaka, T., Oyama, T., and Rahman, K.M. (2009). Melatonin suppresses AOM/DSS-induced large bowel oncogenesis in rats. Chem. Biol. Interact. 177, 128–136.10.1016/j.cbi.2008.10.047Search in Google Scholar PubMed

Tel-Missiry, M. and Abd El-Aziz, A. (2000). Influence of melatonin on proliferation and antioxidant system in Ehrlich ascites carcinoma cells. Cancer Lett. 151, 119–125.10.1016/S0304-3835(99)00366-3Search in Google Scholar PubMed

Tricoire, H., Moller, M., Chemineau, P., and Malpaux, B. (2003). Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod. Reproduction (Suppl.) 61, 311–321.10.1530/biosciprocs.5.023Search in Google Scholar

Tungkum, W., Jumnongprakhon, P., Tocharus, C., Govitrapong, P., and Tocharus, J. (2017). Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines. J. Toxicol. Sci. 42, 63–71.10.2131/jts.42.63Search in Google Scholar PubMed

Vanecek, J. (1998). Cellular mechanism of melatonin action. Physiol. Rev. 78, 687–721.10.1152/physrev.1998.78.3.687Search in Google Scholar

Venegas, C., García, J.A., Escames, G., Ortiz, F., López, A., Doerrier, C., García-Corzo, L., López, L.C., Reiter, R.J., and Acuña-Castroviejo, D. (2012). Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J. Pineal Res. 52, 217–227.10.1111/j.1600-079X.2011.00931.xSearch in Google Scholar PubMed

Vijayalaxmi, Thomas, R.C., Reiter, R.J., and Herman, T.S. (2002). Melatonin: from basic research to cancer treatment clinics. J. Clin. Oncol. 20, 2575–2601.10.1200/JCO.2002.11.004Search in Google Scholar PubMed

Yonei, Y., Hattori, A., Tsutsui, K., Okawa, M., and Ishizuka, B. (2010). Effects of melatonin basics studies and clinical applications. Anti-Aging. Med. 7, 85–91.Search in Google Scholar

Yu, G.M., Kubota, H., Okita, M., and Maeda, T. (2017). The anti-inflammatory and antioxidant effects of melatonin on LPS stimulated bovine mammary epithelial cells. PLoS One 12, e0178525.10.1371/journal.pone.0178525Search in Google Scholar PubMed

Zawilska, J.B., Skene, D.J., and Arendt, J. (2009). Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol. Rep. 61, 383–410.10.1016/S1734-1140(09)70081-7Search in Google Scholar PubMed

Zhang, Y., Yu, X., Chen, L., Zhang, Z., Feng, S. (2017). EZH2 overexpression is associated with poor prognosis in patients with GBM. Oncotarget 8, 565–573.10.18632/oncotarget.13478Search in Google Scholar PubMed PubMed Central

Zheng, X., Pang, B., Gu, G., Gao, T., Zhang, R., Pang, Q., and Liu, Q. (2017). Melatonin inhibits glioblastoma stem-like cells through suppression of EZH2-NOTCH1 signaling axis. Int. J. Biol. Sci. 132, 245–253.10.7150/ijbs.16818Search in Google Scholar PubMed PubMed Central

Zimmermann, R.C., McDougle, C.J., Schumacher, M., Olcese, J., Mason, J.W., Heninger, G.R., and Price, L.H. (1993). Effects of acute tryptophan depletion on nocturnal melatonin secretion in humans. J. Clin. Endocrinol. Metab. 76, 1160–1164.Search in Google Scholar PubMed

Received: 2018-04-25
Accepted: 2018-09-07
Published Online: 2019-01-12
Published in Print: 2019-07-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

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