Melatonin for the prevention and treatment of cancer

Abstract

INTRODUCTION

Melatonin (N-acetyl-5-methoxytryptamine, Figure ​Figure1)1) is an indolic compound secreted primarily by the pineal gland of human and mammals in response to darkness [1]. Except for the pineal, melatonin synthesis is also found in several other organs, including the retina, gastrointestinal tract, skin, bone marrow, and lymphocytes [2]. The process of melatonin biosynthesis and metabolism is shown in Figure ​Figure2,2, and only the primary metabolite 6-sulphatoxymelatonin (aMT6s) is included, because it is commonly used as the maker of circadian melatonin level [3–5]. The synthesis and secretion of melatonin are regulated by the ‘master biological clock’ located in the suprachiasmatic nucleus (SCN) of the hypothalamus [6]. Although melatonin is regulated by central circadian clock, it could also modulate central circadian clock and peripheral oscillators in tissues and organs, which makes melatonin a marker of circadian rhythms [7]. The melatonin level elevates at night and decreases throughout the day. Studies have shown that increased nighttime melatonin levels in the blood could send signals to the body's cells and organs that it is nighttime and help organize target organs and organ systems into appropriate homeostatic metabolic rhythms [8]. Therefore, light at night (LAN) could disrupt the circadian rhythm and the melatonin production [9], which could contribute to the development, promotion, and progression of cancers.

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Figure 1

Structure of melatonin

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Figure 2

The biosynthesis and metabolism process of melatonin

According to the data reported by WHO, cancer is the leading cause of worldwide morbidity and mortality, with approximately 14 million new cases and 8.2 million cancer associated deaths in 2012 [10]. In the USA alone, it's estimated that in 2016, 1,685,210 new cancer cases and 595,690 cancer deaths could occur [11]. Nowadays, patients with cancer mainly count on clinical treatment, e.g. surgery, radiotherapy and chemotherapy. In addition, some natural products showed the potential for prevention and treatment of cancers [12–21]. Studies on cancer and anticancer therapies have attracted great attention.

In the last decades, accumulating evidence has outlined the relevance of melatonin to human physiology and pathology. Now it is well accepted that melatonin is not only a hormone, but also a cell protector [22], involved in immunomodulation, antioxidative processes, and hematopoiesis [23, 24]. Moreover, a bunch of studies have shown that melatonin has important oncostatic properties, through receptor-dependent and receptor-independent mechanisms [25]. The melatonin receptors MT1 (encoded by MTNR1A) and MT2 (encoded by MTNR1B) belong to the G-protein-coupled receptor (GPCR) group [26], and are mainly responsible for mediating the downstream effects of melatonin [27]. For incidence, they are involved in inhibition of adenyl cyclase and cyclic AMP (cAMP), leading to a reduction in uptake of linoleic acid. Melatonin-induced inhibition on linoleic acid uptake is considered as a mechanism of its antiproliferative effects [28]. The receptor-independent mechanisms are associated with antioxidant activity, regulation of apoptosis, tumor metabolism and cancer immunity, inhibition on angiogenesis and migration, and prevention of circadian disruption [25, 29, 30]. Melatonin also showed the potential to be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation [31].

The objective of the present review is to summarize recent discoveries on the oncostatic property of melatonin, classified by hormone-dependent cancers and hormone-independent cancers, and to discuss the mechanisms of action, based on the results of epidemiological research, experimental studies and clinical trials.

EPIDEMIOLOGICAL STUDIES

Several epidemiological studies support a protective role of melatonin in cancer, yet not all the epidemiological studies are consistent (Table ​(Table1).1). Some studies suggested an inverse association between circadian melatonin level and breast cancer incidence. According to a dose-response analysis of observational studies, high artificial LAN exposure was related with an increased risk of breast cancer (RR = 1.17, 95% CI: 1.11-1.23), and risk of breast cancer was reduced by 14% with an increase of 15 ng/mg creatinine in urinary aMT6s (RR = 0.86, 95% CI: 0.78-0.95), with a linear dose-response trend (P-trend = 0.003) [32]. In addition, a case-control study found that female subjects with serum melatonin levels ≤ 39.5 pg/mL had a significantly higher risk of breast cancer incidence (about 15 folds) compared with subjects with levels > 39.5 pg/mL (OR = 14.24; 95% CI = 4.32-46.90). Meanwhile, the GG genotype of the MTNR1b (encoding melatonin receptor MT2) gene rs#10830963 polymorphism significantly elevated the risk of breast cancer by about 21 times more than the CC genotype (OR = 20.67; 95% CI = 4.77-99.33) [33]. Besides, a meta-analysis including 5 prospective case-control studies reported an inverse relationship between breast cancer risk and the highest levels of urinary aMT6s [34]. Another study evaluated the association between breast cancer risk and common single nucleotide polymorphismsin the MTNR1a, MTNR1b, and AANAT (encoding arylalkylamine N-acetyltransferase) genes among 2,073 cases and 2,083 controls, and reported that common genetic variation in the MTNR1a and MTNR1b genes might contribute to breast cancer susceptibility, and the associations might vary with menopausal status [27]. A nested case-control study reported that a higher urinary aMT6s level was significantly associated with a lower risk of breast cancer (OR = 0.62; 95% CI, 0.41-0.95; P(trend) = 0.004) [35]. However, 4 case-control studies suggested there was no evidence that melatonin level was associated with breast cancer risk. A prospective nested case-control study among British women pointed out that no statistically significant differences in urinary aMT6s level between women with breast cancer and healthy women were observed, regardless of menopausal status [36]. Besides, a case-control study nested in the Women's Health Initiative Observational Cohort reported there was no evidence that higher urinary levels of melatonin were inversely related with breast cancer risk in postmenopausal women [37]. Results from another case-control study nested within the Nurses' Health Study II cohort also did not support an overall association between urinary melatonin levels and breast cancer risk [38]. Likewise, no significant association was found between aMT6s level and breast cancer risk (either overall or by menopausal status) in a case-control study nested in the Guernsey III Study [39].

As for cancers other than breast cancer, a case-cohort study reported that men with first morning urinary aMT6s levels below the median possessed a fourfold higher risk of prostate cancer compared with men with levels above the median (HR: 4.04; 95% CI: 1.26-12.98) [40]. In addition, a case-control study pointed out that patients with high melatonin-sulfate levels or a high melatonin-sulfate/cortisol ratio were less likely to have prostate cancer (adjusted OR (aOR) = 0.59, 95% CI: 0.35-0.99; aOR = 0.46, 95% CI: 0.27-0.77) or advanced stage prostate (aOR = 0.49, 95% CI = 0.26-0.89; aOR = 0.33, 95% CI = 0.17-0.62) [41]. A retrospective study found that the serum melatonin levels in women with ovarian cancer were significantly lower compared with control subjects (p < 0.05), indicating that reduction in circulating melatonin level might contribute to the pathogenesis of ovarian cancer [42]. Besides, according to a meta-analysis of RCTs, melatonin significantly improved the complete and partial remission (16.5 vs. 32.6%; RR = 1.95, 95% CI: 1.49-2.54; p < 0.00001), 1-year survival rate (28.4 vs. 52.2%; RR = 1.90; 95% CI: 1.28-2.83; p = 0.001) for solid tumors, and markedly decreased side effects induced by radiochemotherapy, including neurotoxicity, thrombocytopenia, and fatigue. Meanwhile, effects were accordant across different types of cancers [43]. Similarly, another meta-analysis summarizing 21 clinical trials, which all dealt with solid tumors, revealed that melatonin as an adjuvant cancer care with chemotherapy decreased 1-year mortality (RR = 0.60; 95% CI: 0.54-0.67), and reduced chemotherapy-induced symptoms such as asthenia, leucopenia, nausea, vomiting, and hypotension [44]. However, a nested case-control study showed that no obvious association between urinary melatonin level and ovarian cancer risk was observed [45].

It should be noted that in the existing epidemiological studies, the methods of melatonin assessment are not uniformed, since melatonin concentrations were measured in different samples, such as urine, plasma or serum. Moreover, the melatonin concentration in human body changes with circadian rhythm, however, it has not been determined which sample collection time could best reflect the biological effects of melatonin. These differences might partially result in the inconsistence of epidemiological studies. In this case, the laboratory study in cell culture or on animal models might be more clear and direct to assess the anticancer effect of melatonin and investigate the possible mechanisms involved in this process.

EXPERIMENTAL STUDIES

Accumulating evidence from experimental studies has supported the anticancer properties of melatonin. Given the vast number of studies, publications in the PubMed and Web of Science databases were searched and relevant peer-reviewed articles published in English within 5 years were identified.

Other cancers

The anticancer effect of melatonin has also been observed in melanoma. A study revealed that melatonin combined with ER stress (induced by thapsigargin or tunicamycin) decreased cell viability of B16F10 melanoma cells, via the PI3K/Akt/mTOR pathway [176]. In addition, melatonin enhanced the antitumor activity of fisetin in melanoma cells, as shown by enhanced inhibition on cell viability, cell migration and clone formation, as well as the increased apoptosis. The possible mechanism might be through activation of cytochrome c-dependent apoptotic pathway and inhibition of COX-2/iNOS and NF-κB/p300 signaling pathways [177]. In another study, low melatonin concentrations (10⁻⁹-10⁻⁵ M) suppressed proliferation of B16 melanoma cells without inhibition on fibroblasts, while the high concentrations (10-4-10-2 M) inhibited the cell viability of melanoma cells, but the inhibitory activity was not as marked as that on non-tumor cell (3T3 fibroblasts). The ROS production might contribute to melatonin-induced cell viability inhibition at high melatonin concentrations [178].

Melatonin also showed anti-cancer effect on pituitary prolactin-secreting tumor. In a study, melatonin induced apoptosis of prolactinoma tumor cells via inducing mitochondrial dysfunction and inhibiting energy metabolism, both in vivo (male rats) and in vitro (prolactinoma cells) [179]. Elevated levels of four mitochondrial respiratory complexes activities and ATP production were observed in E-2-induced prolactin-secretory tumor cells, and melatonin repressed the activities of mitochondrial respiratory complexes and the production of ATP.

Melatonin has also shown anticancer effect on human leiomyosarcoma (LMS) [180]. Melatonin showed significant inhibitory effects on tissue-isolated human LMS xenografts, by suppressing aerobic glycolysis (Warburg effect) and tumor linoleic acid uptake and other related signaling mechanisms. Melatonin at physiological concentration also inhibited cell proliferation and cell invasion in in vitro cell culture studies. Another study showed that melatonin was able to induce cell death on a human alveolar rhabdomyosarcoma cell line in a dose- and time-dependent manner [181]. Furthermore, melatonin treatment at 150 and 300 μg/30 g bw for 12 consecutive days could induce a very effective oncostatic and cytotoxic activity in mice incubated with Ehrlich ascites tumor cells [182].

Furthermore, melatonin showed anti-apoptotic effects on lymphocytes and neutrophils obtained from rats injected with HL-60 leukemia cells, as shown by significantly inhibiting caspase-3 and -9 activities, and reverting the proportions of lymphocytes, neutrophils, and eosinophils to their basal values [183]. Besides, melatonin induced cell death in human malignant haematological cell lines, via the activation of the extrinsic pathway of apoptosis, regulated by the improvement in expression of the death receptors Fas, DR4 and DR5 and their ligands Fas L and TRAIL [184]. Moreover, a study investigated melatonin's effect on different cancer cells, including pulmonary adenocarcinoma A549 cell, chondrosarcoma sw-1353 cell, glioblastoma A172 cell, and human acute myeloid leukemia HL-60 cell. A dual effect of melatonin on intracellular redox state was found. That is, oncostatic effect of melatonin depended on its ability to induce either an antioxidant environment (leading to an antiproliferative effect in some tumors) or a prooxidant environment (leading to a cytotoxic effect in some tumors) [185].

Melatonin combined with some chemotherapeutic drugs could exert a synergistic toxic effect on A172 malignant glioma cells and brain tumor stem cells [186], via downregulating the expression and function of adenosine triphosphate-binding cassette transporter ABCG2/BCRP, whose overexpression in malignant glioblastomas is responsible for the multidrug resistance and tumor relapse. Besides, melatonin showed synergistic antitumor effect with vincristine and ifosfamide on SK-N-MC human Ewing sarcoma cancer cells, through potentiating extrinsic apoptosis [187].

The anticancer effect of melatonin and possible mechanisms of action are summarized in Table ​Table2,2, Table ​Table33 and Figure ​Figure3,3, and the synergistic effects of melatonin with other chemotherapy or radiotherapy are summarized in Table ​Table44.

Table 2

The in vitro and in vivo effects of melatonin on hormone-dependent cancers

Study Type	Subject	Dose	Main Effect	Possible Mechanisms	Ref.
Breast Cancer
in vitro	CMT-U229 and MCF-7 cells	1 mM	inhibiting cancer cell metastasis	NA	[57]
in vitro	MCF-7/6, MCF-7/Her2.1, and MCF-7/CXCR4 cells	10−9 M	inhibiting cancer cell invasion	down-regulation of the p38 pathway and suppression of MMP-2 and -9 expression and activity	[58]
in vitro	10 canine mammary tumor fragments	0.5, 1, 2, 5, 10 mM	decreasing proliferation and viability and inducing apoptosis	NA	[59]
in vitro	MDA-MB-361 cells	1 mM	inhibiting cell proliferation and inducing apoptosis	COX-2/PGE2, p300/NF-κB, and PI3K/Akt/signaling; activation of Apaf-1/caspase-dependent apoptotic pathway	[60]
in vitro	MCF-7 and MDA-MB-231 cells	1 nM	anti-angiogenesis effect	NA	[56]
in vitro	MCF-7 cells	1 mM	anti-angiogenesis effect	NA	[62]
in vitro	MDA-MB-231 cells	1 mM	anti-angiogenesis effect	NA	[63]
in vitro	T47D cell	20 nM	anti-aromatase effect	acting as a selective estrogen enzyme modulators	[64]
in vitro	in vitro	1 nM	anti-aromatase effect	inhibiting COX expression and activity	[65]
in vitro	breast cancer-associated fibroblasts	10 pM, 1 nM, 10 μM	inhibiting aromatase expression and activity	inhibiting CYP19A1 gene transcription	[66]
in vitro	MCF-7 cells	1 mM	decreasing aromatase activity and expression	interfering with the desmoplastic reaction via downregulating the anti-adipogenic cytokines	[67]
in vitro	MCF-7 cells	1 nM, 100 nM	inhibiting growth of cancer cells	inducing differential expression of miRNA and miRNA-related genes	[68, 69]
in vitro	MCF-7 cells	1 nM	growth inhibition effect on cancer cells	influencing DNA methylation patterns	[70]
in vitro	MCF-7 cells	1 μM	inhibiting cell proliferation and migration	downregulation of miR-24	[71]
in vitro	MCF-7 cells	1 nM, 100 nM and 10 mM	inhibiting cell proliferation	overexpressing of MT1 receptors	[72]
in vitro	MDA-MB-231, BT-20, SK-BR-3 cells	10−9 M	inhibiting proliferation of cancer cell	NA	[73]
in vitro	MCF-7 and MDA-MB-231 cells	0.0001- 1 mm	controlling metastasis	modulation of ROCK-1 expression	[81]
in vivo	athymic nude mice	100 mg/kg bw
in vitro	MDA-MB-231 cells	0.0001-1 mm	decreasing cell viability	anti-angiogenesis effect	[82]
in vivo	athymic nude mice	40 mg/kg bw	reducing tumor size and cell proliferation
in vivo	BALB/c mice	33 mg/L in drinking water	decreasing tumor growth rate induced by LAN	global DNA methylation	[83]
in vivo	rats	human melatonin-rich blood	affecting cancer cell invasion	activating GSK3β	[84]
Prostate Cancer
in vitro	PC-3 cells	1 mM	anti-angiogenesis effect	upregulation of miRNA3195 and miRNA374b	[93]
in vitro	LNCaP, 22Rv1 cells	10−8 M	inhibiting proliferation	MT1 receptor-mediated inactivation of NF-κB	[94, 95]
in vitro	PC-3 cells	1 nM or 1 mM	suppressing HIF-1α accumulation	inactivating sphingosine kinase 1 pathway and scavenging free radicals	[96]
in vitro	multiple cancer cell lines	10 nM-2 mM	reducing proliferative potential	suppressing Sirt1 activity	[98]
in vitro	LNCaP cells	1 mM	sensitizing cancer cells to cytokines-induced apoptosis	causing phenotypic changes, mainly neuroendocrine differentiation	[99]
in vitro	LNCaP, 22Rm1, DU145 and PC3 cells	1 mM	inhibiting proliferation	resynchronizing dysregulated circadian rhythm circuitry	[100]
in vivo	nude rats	amplified by day time blue light	reducing cancer metabolic, signaling, and proliferative activities	inhibiting Warburg effect	[101]
in vivo	mice	4 nM	inhibiting tumor growth	decreasing angiogenesis	[102]
in vivo	nude rats	human melatonin-rich blood (> 100 pg/mL)	dampening signal transduction, metabolic and growth activity in cancer xenografts	melatonin MT1 receptor-mediated mechanism	[103]
in vivo	mice	10 and 20 mg/L in tap water	inhibiting cancer tumorigenesis	suppressing Sirt1 activity	[98]
Ovarian Cancer
in vitro	OVCAR-429 and PA-1 cells	400, 600, and 800 μM	inhibition on tumor growth	delay of G1/S via down-regulation of CDK2 and 4	[106]
in vivo	rats	200 μg/100 g	reducing tumor masses and incidence of adenocarcinomas	NA	[108]
in vivo	rats	200 μg/100 g	reducing tumor masses and inducing apoptosis	upregulation of p53, BAX, and cleaved caspase-3, and enhancement of DNA fragmentation	[109]
in vivo	rats	200 μg/100 g	reducing tumor volume	attenuating the TLR4-induced MyD88- and TRIF-dependent signaling pathways	[110]
in vivo	rats	200 μg/100 g	reducing tumor masses	attenuating Her-2, p38 MAPK, p-AKT, and mTOR Levels	[112]
Cervical Cancer
in vivo	nude rats	500 pM	inhibiting tumor growth	inhibiting aerobic glycolysis and fatty acid metabolic signaling	[115]
in vivo	nude rats	500 pM	suppressing tumor metabolism and proliferation	inhibition of linoleic acid transport and 13-HODE production	[116]

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NA stands for not available.

Table 3

The in vitro and in vivo activities of melatonin on hormone-independent cancers

Study Type	Subjects	Dose	Main Effect	Possible Mechanisms	Ref.
Oral Cancer
in vitro	HSC-3, OECM-1 cells	0.5, 1 mM	anti-metastatic effect	attenuation of MMP-9 expression and activity mediated by decreasing histone acetylation	[121]
in vitro	SCC9 cells	1 mM	decreasing cell viabilities	inhibiting the expression of HIF-1α, VEGF, and ROCK-1 genes	[122]
Liver Cancer
in vitro	HepG2 cells	1 mM	modulating motility and invasiveness	upregulation of TIMP-1 and attenuation of MMP-9 via NF-κB signaling pathway inhibition	[126]
in vitro	HepG2 cells	1 mM	anti-angiogenesis activity	interfering with transcriptional activation of VEGF, via Hif1α and STAT3	[127]
in vitro	HepG2, SMMC-7721 cells	10−9, 10−7, 10−5, 10−3 M	overcoming apoptosis resistance	suppressing survivin and XIAP via the COX-2/PI3K/AKT pathway	[128]
in vitro	HepG2 cells	50 to 2000 μM	pro-apoptotic effect	regulation of Bim by FoxO3a	[129]
in vitro	HepG2 cells	1000 and 2500 μM	inhibiting proliferation	modulation of MT1 membrane receptor and cAMP and ERK activation	[130]
in vivo	HepG2 cells	10−9, 10−7, 10−5, 10−3 M	sensitizing cancer cells to ER stress-induced apoptosis	downregulating the COX-2 expression and the Bcl-2/Bax ratio, elevating level of CHOP	[131]
in vivo	mice	0.5 mg/kg	reversing the circadian clock disturbed by hepatocarcinogenesis	NA	[132]
in vivo	rats	1 mg/kg	attenuating hepatocarcinogenes	activating ER stress	[133]
Renal Cancer
in vitro	Caki-1 and Achn cells	0.5-2 mM	anti-metastatic effect	suppressing Akt-MAPKs pathway and NF-κB DNA-binding activity	[135]
in vitro	Caki cells	0.1, 0.5, or 1 mM	inducing apoptosis	upregulation of Bim expression	[136]
in vitro	Caki cells	1 mM	enhancing apoptosis induced by thapsigargin	ROS-mediated upregulation of CCAAT-enhancer-binding protein homologous protein	[137]
in vitro	Caki cells	1 mM	enhancing apoptosis induced by kahweol	inducing upregulation of p53-upregulated modulator of apoptosis	[138]
Lung Cancer
in vitro	A549 cells	0.1, 0.5, 0.75, 1.0, 2.5, 5.0 mM	suppressing cell migration and viability	JNK/MAPK Pathway	[143]
Gastric Cancer
in vitro	SGC-7901 cells	0.01, 0.1, 1, 3 mM	inhibited HIF-1α accumulation and endogenous VEGF generation	inhibition of melatonin nuclear receptor RZR/RORγ	[147]
in vitro	AGS cells	0.25, 0.5, 1, 2, 4 mM	inhibiting cell viability, clone formation, cell migration and invasion, and inducing apoptosis	activation of JNK and P38 MAPK and the suppression of NF-κB	[149]
in vitro	SGC-7901 cells	10−9-10−3 M	inhibiting cell viability, clone formation, cell migration, and promoting apoptosis	NA	[150]
in vitro	murine MFC cell	4 mM	inhibiting cancer growth	increase of p21 and Bax and decrease of Bcl-2 mediated by membranous melatonin receptors	[151]
in vitro	SGC-7901 cells	10−4 M	inducing cell differentiation	upregulation of endocan, downregulation of alkaline phosphatase and lactate dehydrogenase activities	[153]
in vitro	murine MFC cell	2, 4, 6, 8, 10 mM	promoting apoptosis and inducing cell cycle arrest at the G2/M phase	downregulation of CD4+CD25+ cells and its Forkhead box p3 expression	[152]
in vivo	mice	25, 50, 100 mg/kg	reducing tumor tissue
in vitro	SGC-7901 cells	3 mM	inhibiting angiogenesis	suppressing RZR/RORγ, SENP1, HIF-1α, and VEGF	[148]
in vivo	nude mice	NA	reducing tumor volume and weight and inhibiting proliferation and angiogenesis
in vivo	BALB/c mice	5 mg/kg/twice/week	impeding tumor growth and peritoneal dissemination	inducing ER stress and inhibiting EMT	[154]
Pancreatic Cancer
in vitro	PANC-1 cells	1 mM	inhibiting cell proliferation and angiogenesis	decreasing VEGF	[158]
in vitro	AR42J cells	1 mM	reducing cell viability	inducing changes of mitochondrial activity and activating caspase-3	[159]
Colorectal Cancer
in vitro	HCT 116 cells	10−6 M	decreasing cancer cellular viability	increasing ROS level	[164]
in vitro	HT-29 cells	10−6-10−2 M	antiproliferative effect	the antioxidative and anti-inflammatory actions	[165]
in vitro	LoVo cells	10−4, 10−3, 10−2, 10−1, 1, 2 mM	suppressing cell proliferation and inducing apoptosis	HDAC4 nuclear import mediated by CaMKII inactivation	[166]
in vitro	Caco-2 and T84 cells	0.1, 0.25, 0.5, 1 mM	inhibiting tumor growth and progression	repressing the activation of ET-1	[168]
in vitro	Caco-2 cells	1.56, 0.78 μg/mL	inducing morphological changes in cancer cell	generation of ROS	[169]
in vitro	HCT116 cells	10 μM	activating cell death programs early	inducing G1-phase arrest	[170]
in vivo	mice	1mg/kg bw	inhibiting the progression of colitis-associated colon carcinogenesis	preventing the process of autophagy, alleviating the level of several inflammatory markers, and modulating Nrf2 signaling pathway	[173]
in vivo	rats	10 mg/kg	controlling the preneoplastic patterns	controlling the dysplastic ACF development	[175]
Melanoma
in vitro	B16 cells	10−4-10−2 M	reducing cell viability	promoting ROS production	[178]
Prolactinoma
in vitro	prolactinoma cells	10−5-10−3 M	inducing apoptosis	repressing activities of mitochondrial respiratory complexes and production of ATP	[179]
in vivo	rats	0.25 or 0.50 mg/d
Leiomyosarcoma
in vitro	SK-LMS-1 cells	100 nM-1 pM	repressing cell proliferation and cell invasion	suppression of aerobic glycolysis and survival signaling	[180]
in vivo	nude rats	human melatonin-rich blood	inhibiting tumor proliferative activity
Alveolar Rhabdomyosarcoma
in vitro	RH30 cells	1, 2 mM	inducing cell death	NA	[181]
Ehrlich Ascites Carcinoma
in vivo	mice	5, 10 mg/kg	oncostatic and cytotoxic activity	NA	[182]
Leukaemia
in vivo	Rats injected with HL-60 cells	20 μg/mL in tap water	anti-apoptotic effects on lymphocytes and neutrophils	inhibiting caspase-3 and -9 activity	[183]
in vitro	human malignant haematological cell	1 mM	inducing cell death	activation of the extrinsic pathway of apoptosis	[184]

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NA stand for not available.

Table 4

The synergetic effect of melatonin with other anticancer drugs or radiotherapy

Cancer Category	Study Type	Treatment	Main Effect	Ref.
breast cancer	in vitro	melatonin (0.3 mM) + doxorubicin (0.5 or 1μM)	inducing apoptosis and cell death by activating TRPV1	[74]
breast cancer	in vitro	melatonin (0.5-5 μM) + arsenic trioxide (0.5-5 μM)	enhancing the apoptotic cell death by generation of ROS, upregulation of Redd1 expression, and activation of the p38/JNK pathways	[75]
breast cancer	in vitro	melatonin (3 mM) + puromycin (1 μM)	inhibiting cancer cell viability by inhibiting 45S pre-rRNA and XPO1 and downregulating IPO7, procaspase 3 and Bcl-xL	[76]
breast cancer	in vitro	melatonin (100 μM) + all-trans retinoic acid (1 μM) + Somatostatin (1 μM)	enhancing the growth inhibitory effect	[77]
breast cancer	in vitro	melatonin (1 nM) + vitamin D3 (1 nM)	inhibiting cell proliferation through a TGFβ-1-dependent mechanism	[78]
breast cancer	in vitro	melatonin (1 nM-1 mM) + ionizing radiation (0-12 Gy)	sensitizing cancer cells to radiation by downregulating proteins involved in double-strand DNA break repair	[79]
breast cancer	in vitro	melatonin (1 nM-1 mM) + radiation (8 Gy)	enhancing radiosensitivity of cancer cell by modulation on p53	[80]
breast cancer	in vivo	melatonin (20 mg/L) + L. plantarum LS/07 (8.4 ´ 108 c.f.u.) + inulin (20 g/kg)	augmenting the pro-differentiating, antiproliferative activities via enhancing immunomodulatory action	[85]
breast cancer	in vivo	melatonin (10 mg/kg) + P. acnes (1 ´ 106 cells)	reducing angiogenesis, inhibiting metastasis, inducing apoptosis by stimulating strong Th1-type cytokine antitumor immune response	[86]
breast cancer	in vivo	melatonin + adriamycin	sensitizing tumor to adriamycin	[87]
breast cancer	in vivo	melatonin (20 g/mL) + pravastatin (100 mg/kg)	enhancing the anti-tumor effect of pravastatin	[88]
breast cancer	in vivo	melatonin (0.1 μg/mL) + doxorubicin (6 mg/kg)	inhibiting tumor metabolism, reestablishing the sensitivity of breast tumors to doxorubicin and driving tumor regression by inhibition on circadian-regulated kinase	[89]
breast cancer	in vivo	melatonin (0.1 μg/mL) + tamoxifen (80 mg/kg)	inhibiting tumor metabolism, reestablishing the sensitivity of breast tumors to tamoxifen and driving tumor regression by inhibition on circadian-regulated kinase	[90]
ovarian cancer	in vitro	melatonin (0-2 mM) + cisplatin (80 μM)	enhancing cisplatin-induced apoptosis by inactivation of ERK/p90RSK/HSP27 cascade	[107]
cervical cancer	in vitro	melatonin (1 mM) + cisplatin (20 μM)	reducing cell viability and enhancing cytotoxicity of cisplatin by ROS overproduction and enlarged DNA fragmentation	[114]
endometrial cancer	in vivo	melatonin (25 μg/mL) + estrogen	decreasing endometrial proliferation and preventing the appearance of cellular atypia	[119]
lung cancer	in vitro	melatonin (0.1 mM) + UV irradiation	enhancing apoptosis induced by UV irradiation	[142]
lung cancer	in vitro	melatonin (1 mM) + berberine (100 μM)	sensitizing cancer cells to berberine via activation of caspase/Cyto C and inhibition of AP-2β/hTERT, NF-κB/COX-2 and Akt/ERK signaling pathways	[140]
lung cancer	in vitro	melatonin (1 mM) + gefitinib (1μM)	downregulating EGFR phosphorylation and inducing apoptosis by sensitizing TKI-resistant cell to gefitinib	[144]
pancreatic cancer	in vitro	melatonin (1.5 mM) + gemcitabine (20 mM)	inducing apoptosis and necrosis by modulation of Bcl-2/Bax balance	[160]
	in vivo
pancreatic cancer	in vitro	melatonin (1 mM) + 5-fluorouracil (1 mM) or cisplatin (20 μM) or doxorubicin (1μM)	enhancing cytotoxicity and apoptosis by increasing intracellular ROS production and enhancing mitochondrial membrane depolarization	[161]
pancreatic cancer	in vivo	melatonin (20 μg/mL) + capecitabine (50 mg/d)	improving antitumor activity by decreasing lipoperoxide levels and increasing antioxidant activity	[162]
colorectal cancer	in vitro	melatonin (1.0 mM)) + ursolic acid (20 μM)	enhancing antiproliferative and pro-apoptotic activities by regulation of cytochrome c/caspase, MMP9/COX-2, and p300/NF-κB signaling pathways	[172]
melanoma	in vitro	melatonin (0.1-1.0 mM) + thapsigargin (1 μM) or tunicamycin (5 μg/mL)	decreasing cell viability via regulation of the PI3K/Akt/mTOR pathway	[176]
melanoma	in vitro	melatonin (0.1-1.0 mM) + fisetin (20μM)	enhancing the antitumor activity by inhibition of COX-2/iNOS and NF-κB/p300 signaling pathways	[177]
glioblastomas	in vitro	melatonin (1 mM) + temozolomide (0–2 mM) or doxorubicin (0–50 mM) or mitoxantrone (0–50 mM)	inducing a synergistic toxic effect on cancer cell by increasing methylation of the ABCG2/BCRP promoter	[186]
Ewing sarcoma	in vitro	melatonin (1 mM) + vincristine (5 nM) or ifosfamide (0.5 mM)	exerting synergistic antitumor effect by potentiating extrinsic apoptotic pathway	[187]

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Figure 3

Mechanisms of the anticancer effect of melatonin

→stands for promotion, - stands for regulation, and —stands for inhibition.

CLINICAL TRIALS

In clinical trials concerning melatonin's anticancer effect, melatonin was mainly used as an adjuvant therapy with other chemotherapeutic drugs. Several clinical studies suggested that melatonin could enhance the therapeutic efficacy and reduce the toxicities of other anticancer drugs, as shown by increased partial response, induced tumor regression, higher survival rate and relieved symptoms of side effects. According to a clinical trial, treatment of low-dose subcutaneous interleukin-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40 mg/day orally) significantly increased 1 year survival rate of patients with metastatic colorectal cancer, compared with supportive care alone (9/25 vs. 3/25, p < 0.05) [188]. In a phase-II study including 14 patients with metastatic breast cancer, an oral 20 mg/day of melatonin starting 7 days before tamoxifen therapy achieved a partial response in 4/14 (28.5%) patients, caused a relief of anxiety in most patients, and did not enhance the toxicity of tamoxifen. Besides, serum levels of IGF-1 were decreased by the combination therapy [189]. Another clinical trial also reported that melatonin could enhance the efficacy of chemotherapy and reduce the toxicity in patients with metastatic solid tumor [190]. Besides, a clinical study evaluated the effect of a concomitant administration of melatonin (20 mg/day orally in the evening) on metastatic NSCL cancer patients receiving a chemotherapeutic regimen consisting of cisplatin and etoposide. Patients receiving concomitant melatonin showed higher overall tumor regression rate and 5-year survival, with a better tolerance to chemotherapy [191]. Similarly, concomitant melatonin with irinotecan achieved a higher percent of disease-control on metastatic colorectal cancer patients than irinotecan alone, because partial response and stable disease were obtained by more patients [192].

Besides, several studies reported that melatonin might be able to improve the sleep and quality of life in patients with breast cancer. In a prospective phase II trial, bedtime melatonin was associated with a significant improvement in objective sleep quality, subjective sleep, sleep fragmentation and quantity, fatigue severity, global quality of life, and social and cognitive functioning scales [193]. Besides, a double-blind, placebo-controlled, randomized clinical trial pointed out that the risk of developing depressive symptoms in subjects who received 6 mg oral melatonin was significantly lower than that of subjects who took placebo [194]. Furthermore, the secondary outcomes of this trial reported that 6 mg oral melatonin administration approximately 1 hour before bedtime led to significantly improved sleep efficiency and reduced wake after sleep onset for the 2-week postoperative period [195]. Another randomized, placebo-controlled trial claimed that compared to subjects on placebo, subjects who received melatonin reported significantly increases in subjective sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) [196]. Another study showed that melatonin combined with somatostatin, retinoids, vitamin D₃ and low dose of cyclophosphamide preformed a positive action in terms of efficacy and survival of breast cancer in human [197]. However, a double-blind, placebo-controlled study reported that short-term melatonin treatment did not produce any significant influence on the estradiol and IGF-1/IGBBP-3 levels in women with a prior history of stages 0-III breast cancer [198]. Furthermore, another double-blind placebo-controlled crossover trial which included 72 patients suggested that 20 mg oral melatonin administration was not able to improve fatigue or other symptoms in patients with advanced cancer [199].

Collectively, in clinical trials, melatonin showed the ability to enhance the therapeutic effect of various anticancer drugs. Meanwhile, melatonin might help improving the sleep and life quality of cancer patients.

CONCLUSIONS AND PROSPECTS

The effects of melatonin on cancers have been widely studied, with a focus on hormone-dependent cancers. Epidemiological studies concerning the association between body circadian melatonin levels and cancer incidence led to controversial conclusions, which were either significant association or no association at all. Numerous experimental studies have indicated an oncostatic role of melatonin in various cancers, such as breast, ovarian, prostate, oral, gastric, and colorectal cancers. The underlying mechanisms include several molecular pathways, which are associated with antioxidant activity, modulation of melatonin receptors MT1 and MT2, regulation of apoptosis, pro-survival signaling and tumor metabolism, inhibition of angiogenesis, invasion and metastasis, and induction of epigenetic alteration. Melatonin also showed the potential to be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. In clinical trials, melatonin showed the ability to enhance the therapeutic effect of various anticancer drugs, and might help improving the sleep and life quality of cancer patients. Overall, the impressive efficacy and safety of melatonin support it as a promising agent for the prevention and treatment of cancers.

In the future, several aspects about melatonin's anticancer action should be further investigated. For epidemiological studies, the main problem is the inconsistence of results. This might be because different kinds of sample, sample collection time and assessment methods of melatonin were used. Therefore, different assessment methods of melatonin need to be compared, and the most reliable one should be adopted in future studies. Besides, the effects of different kinds of sample (such as urine, plasma or serum) on the results need to be studied, and the same type of sample should be used. Furthermore, the most appropriate sample collection time should be determined because the melatonin concentration in human body changes with circadian rhythm. For experimental studies, it should be noted that melatonin regulates the physiology and molecular biology of cells through a variety of mechanisms, and cancer is a heterogeneous disease. Therefore, the anticancer efficacy of melatonin was not limited to the aforementioned mechanisms of action. For incidence, autophagy is a prominent feature of programmed cell death, and studies of melatonin's effect on autophagy in cancer cells are very few. Besides, beneficial effects of melatonin against mitochondrial dysfunction in different pathologies have also been described in literature. Thus, there is a possibility that melatonin's oncostatic effect is linked to mitophagy. However, the related researches in this topic are insufficient. Thus, future research might encompass melatonin's effect on autophagy and mitophagy, and other molecular mechanisms involved in its anticancer action. For clinical trials, melatonin's enhancing effect on more anticancer drugs should be further assessed. In addition, its direct effect on patients with manifest cancer should be studied by exogenous melatonin administration to find its oncostatic effects on some cancers and provide information on dosage and long-term safety of melatonin. Moreover, mechanisms of action should be investigated further.

Acknowledgments

Abbreviations

Footnotes

REFERENCES