Role and Therapeutic Potential of Melatonin in Various Type of Cancers

Figures & data

Figure 1 Conserved nature of MLT from prokaryotes to eukaryotes.

Figure 2 Multifunctional aspects of MLT.

Figure 3 Tumor suppressive properties of MLT on lung cancer by targeting family of transcription factors.

Figure 4 Molecular mechanism of anticancer activity of MLT in breast cancer cells.

Figure 5 MLT targets mitochondria mediated apoptosis in prostate cancer cells.

Figure 6 Inhibitory effects of MLT on endothelin.

Figure 7 Molecular mechanism of anticancer activity of MLT on ovarian cancer.

Figure 8 Ubiquitous anticancer and antiangiogenic effect of MLT.

Table 1 The in vitro and in vivo Effects of Melatonin on Various Type of Cancers

Type of Cancer	Type of Experiments Performed	Objective of the Study	Significance of the Study	Reference
Lung	Tumor inoculation and melatonin treatment (1.25 mg/kg/night) were performed 2 months after pinealectomy	Female BD2F1 mice with subcutaneous propagation of Lewis lung carcinoma	Melatonin treatment decreased metastasis with consequent restoration of thymic efficiency	[^Citation214]
Lung	30 NSCLC patients before and after treatment with standard chemotherapy (cisplatin plus vinorelbine) and 63 healthy volunteers	Melatonin levels were measured in blood and urine samples	Melatonin, its precursor tryptophan, and its major metabolite, 6-sulfatoxymelatonin concentrations were significantly lower in cancer patients, in comparison with healthy subjects	[^Citation215]
Lung	17 patients with stages I and II of untreated NSCLC, 17 patients with stages III and IV of untreated NSCLC, and 17 controls	Melatonin level was measured in blood samples	Melatonin levels were lower in the patients with NSCLC than in normal subjects	[^Citation216]
Lung	SK-LU-1 NSCLC cell line	Cells were treated with Melatonin (1, 2 mM) + cisplatin (10–200 μM) (48 h in culture)	Melatonin potentiate the effect of cisplatin and reduce the IC50 concentration of cisplatin	[^Citation38]
Lung	A549 cells and healthy human lymphocytes	Combination of melatonin (50 μM) and various concentrations of irinotecan (7.5, 15, 30, and 60 μM)	The combination treatment specific to cancer cells not healthy lymphocytes	[^Citation118]
Lung	A549 cells	Melatonin (0.1, 1 mM) + doxorubicin (0.1, 1 microg/mL)	Melatonin increases cytotoxicity and apoptosis with doxorubicin	[^Citation217]
Lung	Female C57B/6 mice with subcutaneous propagation of Lewis lung carcinoma H1299 and A549 cells	Melatonin (1 mg/kg) + cyclophosphamide (40, 160 mg/kg) + etoposide (20, 40 mg/kg)	Melatonin can rescue myeloid progenitor cells from chemotherapy-induced apoptosis	[^Citation218]
Lung	H1299 and A549 cells	Melatonin (1 mM) + berberine (20μM to 200 μM)	Melatonin sensitized NSCLC cells to berberine and enhanced apoptosis	[^Citation219]
Lung	Untreatable metastatic NSCLC or GI cancers (No of patients 846)	Melatonin (20 mg/day) + IL-2 (3 million IU/day, 5 days/week, 4 weeks) + supportive care	The combination treatment reduces tumor regressions	[^Citation220]
Lung	Advanced lung adenocarcinoma No of patients 23	Melatonin (20 mg/day) + somatostatin (1–3 mg/day) + Retinoids (5 mL) + Vitamin D (0.3 mg/day) + bromocriptine (2.5 mg/day) + cyclophosphamide (150 mg/day)	Combination treatments increases 95 days of survival of patients	[^Citation221]
Lung	Untreated metastatic NSCLC (No of patients 147)	Melatonin (20 mg/day) + cisplatin plus etoposide or gemcitabine	Combination treatment increases over all survival of patients for 2 years and also tumor regression was observed	[^Citation34]
Lung	Untreated metastatic NSCLC (No of patients 100)	Melatonin (20 mg/day) + cisplatin (20 mg/m2/day) + etoposide (100 mg/m2/day)	Overall survival of patients was increased and also tumor regression rate was observed The percent of 1-year survival was significantly higher in patients treated with melatonin plus chemotherapy	[^Citation32]
Lung	Advanced NSCLC	Melatonin (20 mg/day) + cisplatin (20 mg/m2/day) + etoposide (100 mg/m2/day)	The inhibitory action of melatonin on mammary cancer estrogen-positive cell lines is depends on its ability to regulate either the synthesis of estrogens or estrogen signaling pathways	[^Citation222]
Breast	In vitro	Cancer estrogen-positive cell lines treated with 1nM melatonin 1nM melatonin	Decreases the levels of ERα in in vitro experiments in MCF-7 cells	[^Citation223]
Breast	In vitro	MCF-7 cells treated with (1 nM)	Combination of melatonin and troglitazone induces apoptosis in MDA-MB-231	[^Citation224]
Breast	In vitro	Melatonin (1mM) and troglitazone	Combination of melatonin and DMBA reduced tumor incidence and decreased the quantity of invasive and in situ carcinomas in a rat model	[^Citation225]
Breast	In vivo	Melatonin (500 mg/day, 2 weeks prior to DMBA during 20 weeks, injected at late afternoon) and resveratrol	Combined with doxorubicin, and melatonin enhanced cancer cells apoptosis in vivo in rats bearing breast tumors and also increases survival rate.	[^Citation226]
Breast	In vivo	The animals treated with both doxorubicin plus melatonin (10 mg/kg of body weight, daily injected during 15 days)	Increases survival rate and reduce tumor level	[^Citation227]
Breast	In vitro	MCF-7 cells treated with doxorubicin and melatonin	Combination of doxorubicin and melatonin had a synergic effect on apoptosis and mitochondrial oxidative stress.	[^Citation228]
Prostate	In vivo	Rats were treated with melatonin (dose of 150 mg/100 g of body weight, administered for 4 weeks)	Melatonin treated rats showed significant decrease in the ventral prostate weight in castrated and castrated-testosterone-treated rats	[^Citation229]
Prostate	In vitro	Prostate cancer cells treated with, a physiological dose of melatonin (1 nM)	Melatonin treatment attenuated the growth of the human androgen-sensitive prostatic tumor cell line LNCaP in vitro	[^Citation230]
Breast	In vitro	Breast cancer cell lines CMT-U229 and MCF-7 treated with 1mM melatonin	Inhibits metastasis	[^Citation64]
Breast	In vitro	MCF-7/6, MCF-7/Her2.1, and MCF-7/CXCR4 cells treated with 10–9 M of melatonin	Inhibiting cancer cell invasion by down-regulation of the p38 pathway and suppression of MMP-2 and −9 expression and activity	[^Citation227]
Breast	In vivo	Athymic nude mice treated with melatonin at concentration of 40 mg/kg	Melatonin inhibits angiogenesis by reducing cell proliferation and tumor size	[^Citation231]
Breast	In vivo	BALB/C mice were treated with melatonin 33mg/L	Melatonin decreases tumor size by the mechanism regulation global DNA methylation	[^Citation232]
Prostate	In vivo	Mice were treated with 4 nM of melatonin	Melatonin inhibits angiogenesis and inhibits growth	[^Citation96]
Prostate	In vivo	Mice were treated with 10 and 20 mg/L	Melatonin inhibits tumorigenesis by suppressing SIRT1 activity	[^Citation233]
Ovarian cancer	In vitro	Ovarian cancer cell lines such as OVCAR-429 and PA-1 cells treated with various concentrations of 400, 600, and 800 μM melatonin	Inhibiting angiogenesis by delay of G1/S via down-regulation of CDK2 and 4	[^Citation194]
Ovarian cancer	In vivo	Rats were treated with 200 μg/100 g melatonin	Reducing tumor size and apoptosis by various mechanisms such as upregulation of p53, BAX, and cleaved caspase-3, and enhancement of DNA fragmentation; attenuating the TLR4-induced MyD88- and TRIF-dependent signaling pathways; attenuating Her-2, p38 MAPK, p-AKT, and mTOR Levels	[^Citation190,Citation193,Citation234]
Cervical cancer	In vivo	Nude rats were treated with 500 pM melatonin	Melatonin inhibiting tumor growth suppressing tumor metabolism and proliferation through inhibiting aerobic glycolysis and fatty acid metabolic signaling	[^Citation235,Citation236]

Mocchegiani E, Perissin L, Santarelli L, et al. Melatonin administration in tumor-bearing mice (intact and pinealectomized) in relation to stress, zinc, thymulin and IL-2. Int J Immunopharmacol. 1999;21(1):27–46. doi:10.1016/s0192-0561(98)00067-8

 PubMed Web of Science ®Google Scholar

Hu S, Shen G, Yin S, Xu W, Hu B. Melatonin and tryptophan circadian profiles in patients with advanced non-small cell lung cancer. Adv Ther. 2009;26(9):886–892. doi:10.1007/s12325-009-0068-8

 PubMed Web of Science ®Google Scholar

Mazzoccoli G, Carughi S, De Cata A, La Viola M, Vendemiale G. Melatonin and cortisol serum levels in lung cancer patients at different stages of disease. Med Sci Monit. 2005;11(6):Cr284–288.

 PubMed Web of Science ®Google Scholar

Plaimee P, Weerapreeyakul N, Barusrux S, Johns NP. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif. 2015;48(1):67–77. doi:10.1111/cpr.12158

 PubMed Web of Science ®Google Scholar

Kontek R, Nowicka H. The modulatory effect of melatonin on genotoxicity of irinotecan in healthy human lymphocytes and cancer cells. Drug Chem Toxicol. 2013;36(3):335–342. doi:10.3109/01480545.2012.737805

 PubMed Web of Science ®Google Scholar

Fic M, Podhorska-Okolow M, Dziegiel P, et al. Effect of melatonin on cytotoxicity of doxorubicin toward selected cell lines (human keratinocytes, lung cancer cell line A-549, laryngeal cancer cell line Hep-2). In Vivo. 2007;21(3):513–518.

 PubMed Web of Science ®Google Scholar

Maestroni GJ, Covacci V, Conti A. Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Cancer Res. 1994;54(9):2429–2432.

 PubMed Web of Science ®Google Scholar

Lu JJ, Fu L, Tang Z, et al. Melatonin inhibits AP-2β/hTERT, NF-κB/COX-2 and Akt/ERK and activates caspase/Cyto C signaling to enhance the antitumor activity of berberine in lung cancer cells. Oncotarget. 2016;7(3):2985–3001. doi:10.18632/oncotarget.6407

 PubMedGoogle Scholar

Lissoni P, Brivio F, Fumagalli L, et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res. 2008;28(2b):1377–1381.

 PubMed Web of Science ®Google Scholar

Norsa A, Martino V. Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status. Cancer Biother Radiopharm. 2007;22(1):50–55. doi:10.1089/cbr.2006.365

 PubMed Web of Science ®Google Scholar

Lissoni P. Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathol Biol. 2007;55(3–4):201–204. doi:10.1016/j.patbio.2006.12.025

 PubMedGoogle Scholar

Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003;35(1):12–15. doi:10.1034/j.1600-079x.2003.00032.x

 PubMed Web of Science ®Google Scholar

Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res. 1997;23(1):15–19. doi:10.1111/j.1600-079x.1997.tb00329.x

 PubMed Web of Science ®Google Scholar

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):118–128. doi:10.1016/j.cdp.2006.03.002

 PubMedGoogle Scholar

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):1681–1690. doi:10.1210/mend.8.12.7708056

 PubMedGoogle Scholar

Korkmaz A, Tamura H, Manchester LC, Ogden GB, Tan D-X, Reiter RJ. Combination of melatonin and a peroxisome proliferator-activated receptor-γ agonist induces apoptosis in a breast cancer cell line. J Pineal Res. 2009;46(1):115–116. doi:10.1111/j.1600-079X.2008.00635.x

 PubMed Web of Science ®Google Scholar

Kisková T, Ekmekcioglu C, Garajová M, et al. A combination of resveratrol and melatonin exerts chemopreventive effects in N-methyl-N-nitrosourea-induced rat mammary carcinogenesis. Eur J Cancer Prev. 2012;21(2):163–170. doi:10.1097/CEJ.0b013e32834c9c0f

 PubMed Web of Science ®Google Scholar

Mao L, Yuan L, Slakey LM, Jones FE, Burow ME, Hill SM. Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. Breast Cancer Res. 2010;12(6):R107. doi:10.1186/bcr2794

 PubMed Web of Science ®Google Scholar

Koşar PA, Nazıroğlu M, Övey İS, Çiğ B. Synergic effects of doxorubicin and melatonin on apoptosis and mitochondrial oxidative stress in MCF-7 breast cancer cells: involvement of TRPV1 channels. J Membr Biol. 2016;249(1–2):129–140. doi:10.1007/s00232-015-9855-0

 PubMed Web of Science ®Google Scholar

Debeljuk L, Feder VM, Paulucci OA. Effects of melatonin on changes induced by castration and testosterone in sexual structures of male rats. Endocrinology. 1970;87(6):1358–1360. doi:10.1210/endo-87-6-1358

 PubMedGoogle Scholar

Lupowitz Z, Zisapel N. Hormonal interactions in human prostate tumor LNCaP cells. J Steroid Biochem Mol Biol. 1999;68(1–2):83–88. doi:10.1016/s0960-0760(98)00164-2

 PubMed Web of Science ®Google Scholar

Gonçalves Ndo N, Colombo J, Lopes JR, et al. Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines. PLoS One. 2016;11(3):e0150407. doi:10.1371/journal.pone.0150407

 PubMed Web of Science ®Google Scholar

Jardim-Perassi BV, Arbab AS, Ferreira LC, et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One. 2014;9(1):e85311. doi:10.1371/journal.pone.0085311

 PubMed Web of Science ®Google Scholar

Schwimmer H, Metzer A, Pilosof Y, et al. Light at night and melatonin have opposite effects on breast cancer tumors in mice assessed by growth rates and global DNA methylation. Chronobiol Int. 2014;31(1):144–150. doi:10.3109/07420528.2013.842925

 PubMed Web of Science ®Google Scholar

Paroni R, Terraneo L, Bonomini F, et al. Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling. J Pineal Res. 2014;57(1):43–52. doi:10.1111/jpi.12142

 PubMed Web of Science ®Google Scholar

Jung-Hynes B, Schmit TL, Reagan-Shaw SR, Siddiqui IA, Mukhtar H, Ahmad N. Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. J Pineal Res. 2011;50(2):140–149. doi:10.1111/j.1600-079X.2010.00823.x

 PubMed Web of Science ®Google Scholar

Shen CJ, Chang CC, Chen YT, Lai CS, Hsu YC. Melatonin suppresses the growth of ovarian cancer cell lines (OVCAR-429 and PA-1) and potentiates the effect of G1 arrest by targeting CDKs. Int J Mol Sci. 2016;17(2):176. doi:10.3390/ijms17020176

 PubMed Web of Science ®Google Scholar

Chuffa LG, Fioruci-Fontanelli BA, Mendes LO, et al. Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer. BMC Cancer. 2015;15:34. doi:10.1186/s12885-015-1032-4

 PubMed Web of Science ®Google Scholar

Chuffa LG, Alves MS, Martinez M, et al. Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma. Endocr Relat Cancer. 2016;23(2):65–76. doi:10.1530/erc-15-0463

 PubMed Web of Science ®Google Scholar

Ferreira SG, Peliciari-Garcia RA, Takahashi-Hyodo SA, et al. Effects of melatonin on DNA damage induced by cyclophosphamide in rats. Braz J Med Biol Res. 2013;46(3):278–286. doi:10.1590/1414-431x20122230

 PubMed Web of Science ®Google Scholar

Dauchy RT, Dauchy EM, Hanifin JP, et al. Effects of spectral transmittance through standard laboratory cages on circadian metabolism and physiology in nude rats. J Am Assoc Lab Anim Sci. 2013;52(2):146–156.

 PubMed Web of Science ®Google Scholar

Dauchy RT, Dauchy EM, Mao L, Belancio VP, Hill SM, Blask DE. A new apparatus and surgical technique for the dual perfusion of human tumor xenografts in situ in nude rats. Comp Med. 2012;62(2):99–108.

 PubMed Web of Science ®Google Scholar