Therapeutic targets of cancer drugs: Modulation by melatonin

Milad Moloudizargari a, Fatemeh Moradkhani b, Shirin Hekmatirad c, Marjan Fallah d,
Mohammad Hossein Asghari e,*, Russel J. Reiter f,*
a Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
b Department of Medical Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
c Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
d Medicinal Plant Research Centre, Faculty of Pharmacy, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
e Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
f Department of Cell Systems and Anatomy, Long School of Medicine, UT Health, San Antonio, TX, USA

Abstract

The biological functions of melatonin range beyond the regulation of the circadian rhythm. With regard to cancer, melatonin’s potential to suppress cancer initiation, progression, angiogenesis and metastasis as well as sensitizing malignant cells to conventional chemo- and radiotherapy are among its most interesting effects. The targets at which melatonin initiates its anti-cancer effects are in common with those of a majority of existing anti- cancer agents, giving rise to the notion that this molecule is a pleiotropic agent sharing many features with other antineoplastic drugs in terms of their mechanisms of action. Among these common mechanisms of action are the regulation of several major intracellular pathways including mitogen-activated protein kinase (MAPK), extra- cellular signal–regulated kinase (ERK) and protein kinase B (AKT/PKB) signaling. The important mediators affected by melatonin include cyclins, nuclear factor-κB (NF-κB), heat shock proteins (HSPs) and c-Myc, all of which can serve as potential targets for cancer drugs. Melatonin also exerts some of its anti-cancer effects via inducing epigenetic modifications, DNA damage and mitochondrial disruption in malignant cells. The regulation of these mediators by melatonin mitigates tumor growth and invasiveness via modulating their downstream responsive genes, housekeeping enzymes, telomerase reverse transcriptase, apoptotic gene expression, angio- genic factors and structural proteins involved in metastasis. Increasing our knowledge on how melatonin affects its target sites will help find ways of exploiting the beneficial effects of this ubiquitously-acting molecule in cancer therapy. Acknowledging this, here we reviewed the most studied target pathways attributed to the anti- cancer effects of melatonin, highlighting their therapeutic potential.

1. Melatonin biogenesis and cancer

Melatonin, N-acetyl-5-methoxytryptamine, is the major secreted product of the pineal gland [1]. This small molecule is also synthetized by other organs such as the gastrointestinal tract, kidneys, retina and the skin [2,3]. It has been also proposed that the mitochondria of perhaps all normal cell types are capable of producing melatonin [4–8]. Melatonin synthesis is initiated after the hydrolysis of tryptophan into 5-hydroxy- tryptophan by the tryptophan-5-hydroxylase, the product of which is converted to serotonin by 5-hydroxytryptophan decarboxylase. Seroto- nin is then converted to N-acetylserotonin by the action of arylalkyl- amine-N-acetyltransferase and finally to melatonin by acetylserotonin- O-methyltransferase [9].

With the exception of the retina and the pineal gland, melatonin from all other sources is produced independent of the environmental light- –dark cycles and mostly acts in paracrine and autocrine manners [10,11]. In addition to circadian rhythm regulation, melatonin exerts a wide range of biological effects such as protection against toxic agents [12] and immunoregulation, making it a promising agent to be poten- tially used in autoimmune diseases [13]. Melatonin has also been shown to act as a modulator of brown adipose tissue [14] and as a potent antioxidant either via its direct radical scavenging activity or by means of its indirect induction of antioxidant enzyme expression [15–17]. Melatonin and its metabolites have high safety profiles and have proven beneficial in many pathological conditions [18,19]. As an example, a great deal of evidence shows that melatonin can efficiently reduce cancer initiation and progression [20]. Some of the biological effects carried out by melatonin are initiated following its coupling with its receptors, which exist both on the cellular membrane and possibly in the nucleus of the cells in which it is synthetized in both healthy and ma- lignant cells [5,21,22]. Other actions of melatonin are receptor inde- pendent. In some cases, physiological concentrations of melatonin are capable of suppressing cancer cell proliferation [23,24]. A major piece of evidence on the anti-cancer properties of melatonin that has already been confirmed by several meta-analyses and randomized trials is the higher risk of cancer development among night shift workers whose physiological rhythm of melatonin synthesis is dampened [15,25]. Not only does the co-administration of melatonin and anti-cancer drugs in- crease the efficacy of chemotherapeutic regimens, but also reduces the associated adverse effects [26–28]. In fact, melatonin induces cytotoxic effects in malignant cells while protecting normal cells from chemotherapy-induced damage [29]. In a clinical trial on patients suffering from non-small cell lung cancer or gastrointestinal cancer, a therapeutic regimen combining chemotherapy and melatonin led to a more effective tumor suppression and increased the 2-year survival of the patients [30].

Melatonin exerts its cytotoxic effects in cancer cells through pro-oxidant properties under certain conditions, which give rise to reac- tive oxygen species (ROS). This pro-oxidant effect of melatonin is mediated by DNA damage induced by ROS, which is less likely to be tolerated by cancer cells compared to normal cells. Cancer cells expe- rience more oxidative stress, due to the changes in their metabolic ac- tivity and the elevated ROS production. This is why cancer cells are more vulnerable to additional amounts of ROS than healthy cells. As a result, unlike normal cells, melatonin increases apoptosis in tumor cells [31]. Apoptosis, in general, consists of two intrinsic and extrinsic pathways, among which the former is related to the release of cytochrome C from mitochondria and caspase recruitment. Both the intrinsic and extrinsic stimuli are capable of triggering an internal apoptotic pathway. This is while the external pathway is independent of mitochondria and is initiated by the external stimuli [32]. In a study by Kocyigit et al., melatonin, especially at high doses, decreased NF-κB plus BCL2 expression and increased P53, P21, Bax and caspase 3 expression. DNA damage leads to the activation of P53, resulting in the cessation of cell cycle at the G1 phase and induction of apoptosis [33]. The anti- proliferative effects of melatonin, mediated by the modulation of mitochondrial respiration, are mainly observed in cancer cells whose metabolism relies on mitochondrial metabolism, while those with high glycolytic profiles seem to be resistant to the mitochondrial effects of melatonin [32].
The beneficial biological effects of melatonin are either mediated through the activation of its receptors or in a receptor-independent manner. Both the membrane-bound and the nuclear receptors of mela- tonin may be involved in the initiation of its downstream signaling pathways. Whether the membrane-bound or the nuclear receptors of melatonin are activated is mainly dependent upon the effective con- centration of melatonin, which is a key determining factor. Melatonin receptors include MT1, MT2 and MT3. Being their natural agonist, melatonin has a high affinity for the G protein-coupled receptors (GPCRs), MT1 and MT2. This is while MT3 is neither a GPCR nor has high-affinity binding to melatonin [21]. MT1activates pertussis toxin- sensitive G proteins including Gi2, Gi3 and Gq/11, which subse- quently suppresses cyclic adenosine 3′,5′-monophosphate (cAMP) production. This subsequently results in decreased CREB phosphorylation,which per se, is mediated by the inhibition of cAMP-dependent protein kinase (PKA) activation [34,35]. Among the nuclear receptors of mela- tonin is RZR/ROR, which in its monomeric form regulates gene expression via binding to gene promotors [36]. A recent study also shows that melatonin may bind to the nuclear vitamin D receptor [5–8]. There is a great deal of evidence indicating that melatonin can beneficially interfere with mechanisms involved in cancer development and progression; illustrated in detail in Fig. 1. Therapeutic targets of melatonin and several clinical trials have also been carried out to evaluate the beneficial effects of melatonin in cancer patients, which are summarized in Tables 1 and 2. In the following sections, the effects of melatonin on the most studied therapeutic targets of cancer drugs will be summarized to provide a better understanding of the underlying mechanisms governed by melatonin and its potential implementation in cancer treatment.

Fig. 1. Modulation of the therapeutic targets of anti-cancer drugs by melatonin. MAP, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase;IKK, Inhibitory-κB Kinase; AKT, protein kinase B; PIK3, phosphoinositide 3-kinases; iNOS, inducible nitric oxide synthase.

2. Cyclin D as a therapeutic target in cancer

The activity of cyclins and cyclin-dependent kinases at specific stages of the cell cycle coordinate DNA replication, cell division and cycle progression [37]. Additionally, they regulate the checkpoints that terminate cell cycle progression in response to DNA damage and mitotic spindle defects. These proteins include D-type cyclins that regulate cyclin-dependent kinase 4 (CDK4) and CDK6 and E-type cyclins, which control the activity of CDK2. The levels of cyclins fluctuate at different stages of the cell cycle, resulting in a strict and time-dependent activity regulation of different kinases. Other ways by which CDKs are regulated include their interactions with catalytic subunits; activating and inhib- iting phosphorylations and the presence of CDK inhibitors of the INK4, CIP and KIP families [38,39]. Abnormal regulation of cyclins can directly lead to tumorigenesis. The underlying evidence comes from the studies in which cyclin D1 inactivation reduced the proliferation of gastrointestinal tumors, in vivo [40], while the overexpression of cyclin D1 caused tumorigenesis via inducing proliferations unresponsive to normal extracellular signals or by overriding checkpoints that ensure the integrity and stability of the genome [41,42]. As a result, cyclins and CDKs have been regarded as potential oncogenes and a large number of reports document their deregulation in cancer [43]. As of now, there are numerous compounds with CDK and Cyclin D1 inhibiting activities, currently undergoing clinical trials as anti-cancer drugs [44–46]. This suggests that this approach is potentially feasible in cancer therapy.

The ability of melatonin to downregulate cyclin D1 and CDKs has been unveiled in several studies. In one experiment, melatonin treat- ment of MCF-7 cells caused the downregulation of cyclin D1, which abrogated the estrogen-induced growth of these cells. This effect was due to melatonin’s repression of a cAMP response element binding site on the cyclin D1 promoter, which ensures estrogen sensitivity. The au- thors suggested that the melatonin’s action on cyclin D1 promoter was mediated by c-jun and activating transcription factor 2 (ATF-2) proteins, which bind to the estrogen-sensitive cAMP response element in the cyclin D1 promoter region. The result of this study provided clear evi- dence for the transcriptional inhibition of cyclin D1 by melatonin [38,47]. Melatonin also blocked 17-beta-estradiol-induced over- expression of cyclin D1 via ROR alpha 1 [47]. Treatment of the MG-63 osteosarcoma cell line with melatonin resulted in a significant increase in the fraction of the cells in G0/G1 phase and the concomitant reduction of cells in the S and G2/M phases. Further analyses uncovered the downregulation of cyclin D1 and CDK4, responsible for the G1 phase checkpoints, and of cyclin B1 and CDK1, related to the G2/M phase. Nevertheless, no repression of cyclin E, CDK2 or cyclin A as controllers of the transition from G1/S to S was observed. It was finally concluded that melatonin could significantly inhibit the proliferation of osteosarcoma cells via the downregulation of the cyclins D1 and B1 as well as CDK4 and CDK1.

The expression and phosphorylation status evaluation of ERK, AKT, JNK and P38 further revealed that melatonin inhibited the phosphory- lation of ERK1/2 without changing its expression [48]. In another interesting study on HCT116 human colorectal cancer cells, melatonin treatment increased the levels of p16INK4A and P21kip1, two inhibitors of cyclin-CDK complexes, downregulated the cyclins E and A, induced cell cycle arrest at G1-phase and decreased the number of cells in the S phase of the cell cycle with a slight increase in the G2/M cell population. Importantly, no repression of the cyclins D or B was observed in this study [49]. Similarly, an increase in p21kip1, downregulation of cyclin D1 and G0/G1 cell cycle arrest were also observed in the SCC25 oral cancer cell line treated with melatonin, which were shown to be the consequences of reducing LSD1 expression by melatonin [50]. Down- regulation of CDKs also seems to be an important mechanism of melatonin-mediated cell proliferation arrest; in a study on hepato- carcinoma cells, melatonin increased p27kip1, an inhibitor of multiple CDKs. Further investigations demonstrated the pivotal role of phos- phorylated Akt (pAKT) and c-myc in the transcriptional and post- translational regulation of p27kip1. Enhanced levels of p27kip1 sup- pressed the expression of cyclin D1 and CDK4/6, which ultimately sensitized the hepato-carcinoma cells to the effects of sorafenib [51]. It is noteworthy that, melatonin was capable of suppressing AKT in human glioma cells via a MAPK-independent pathway [52]. Additionally, melatonin exerted antitumor activity by halting the proliferation of B65 rat dopaminergic neuroblastoma cells beyond G1-phase through the transcription repression of CDK4, CDK2 and cyclin D1 [53]. Similar results were obtained by Jung et al. in which melatonin suppressed the phosphorylation of AKT/mTOR/STAT3, mitigated the expression of cyclin D1 and cyclin E and enhanced the cytotoxic effect of puromycin on MDA-MB-231 breast cancer cells [54]. Reinforcing these findings, melatonin also mitigated m-TOR and AKT phosphorylation in hepatoma H22 cells and subsequently diminished cyclin D1, cyclin E and CDK4/6. A major disadvantage of recent cyclin and CDK inhibitors as chemo- therapeutic agents is their off target toxicity, which has led to their discontinued use [55,56]. As melatonin can selectively inhibit cyclins and CDKs, we suggest further research to be carried out on this molecule.

3. NF-κB and cancer

Nuclear factor-κB (NF-κB) is a protein complex that regulates the transcription of genes involved in cell cycle regulation and cellular metabolism [57]. It consists of p50, p52, p65 (RelA), c-Rel and Rel B [58]. NF-κB activation, heterodimerization and nuclear translocation is modulated by p65 protein. In fact, gene transcription occurs after the coupling of the phosphorylated forms of P65 and P50. Aberrant NF-κB signaling has been detected in many malignancies including thyroid, gastric, prostate and lung cancers [59–62]. It has been shown that gli- oma cells capable of producing more melatonin show better prognosis due to the anti-apoptotic target genes of NF-κB [63]. Resistance to chemotherapy also associates with nuclear localization of NF-κB [64,65]. Melatonin is capable of reducing resistance to chemotherapy and irradiation and excretes its anti-tumor effects via the abrogation of NF-κB signaling pathway [66,67]. In an in vitro study on the anti-tumor effects of melatonin, not only did melatonin increase cytosolic cyto- chrome C and activate caspases, it also diminished phosphorylated NF- κB/p65 and its nuclear translocation [68]. Suppression of NF-κB led to decreased transcription of its downstream genes including interleukin 1 alpha (IL-1α), Bcl-xl, matrix Metallopeptidase 9 (MMP9) and cyclin D1. Moreover, the absence of TNF-α stimulatory effect on NF-κB following co-treatment of human anaplastic thyroid cancer cells with both mela- tonin and TNF-α showed that melatonin could also block (TNF-α)-trig- gered NF-κB activation [68].

Co-treatment with melatonin and curcumin reduced nuclear trans- location of NF-κB with a purposed mechanism that melatonin decreases the upstream kinases, phosphorylated-IκBα (p-IκBα) and phosphorylated IKKβ (p-IKKβ) that activate NF-κB. Although the expression levels of p- IκBα and p-IKKβ showed no significant changes, their protein levels and kinase activities were diminished. In addition, this combination was shown to sensitize malignant cells to the anti-tumor effects of curcumin, arrest the G2/M phase of cell cycle and reduce tumor invasiveness via suppression of MMP-2/9 expression [69].

The transcription factor NF-κB is responsible for expression of inducible nitric oxide synthase (iNOS), which is highly expressed in malignant cells [70]. iNOS not only plays a key role in tumor progression but also functions in tumor response to 5-FU. Similar to the results of other studies on the synergistic effects of melatonin with chemothera- peutic drugs, melatonin increased the anti-proliferative and anti- metastatic effects of 5-FU on colon cancer. Co-administration of 5-FU and melatonin decreased the protein levels of iNOS through phosphor- ylation suppression of cytoplasmic IKKα, IκBα and p65, which led to the enhanced translocation of P50 and P65 to the cytoplasm [71,72]. This was then followed by declined activation of iNOS promotor via activated NF-κB. Likewise, in a similar study, melatonin caused no alterations in IKKα, IκBα and p65 protein levels and could solely interfere with aber- rant NF-κB signaling through modulating the phosphorylation status of this multicomponent protein [72]. Consistent with other investigations, melatonin decreased NF-κB nuclear translocation via suppression of upstream IKK phosphorylation [73]. In another study, the inhibition of IκBa phosphorylation in pancreatic ductal adenocarcinoma overcame gemcitabine-induced NF-κB activation [66]. Melatonin also blocked the alternative pathway of NF-κB activation via decreasing P38 phosphor- ylation, which interrupts the (P38-MAPK)-mediated activation of NF-κB [66]. Surprisingly, treating gastric cancer cells with JNK and MAPK inhibitors interferes with melatonin suppression of P65 phosphorylation and NF-κB nuclear translocation [74]. P38-activated casein kinase 2 (CK-2), in response to ROS, triggered the phosphorylation of multiple sites of IκBα and substantially activated the NF-κB pathway leading to pulmonary tumor metastasis [75]. Western blot analysis in renal cancer showed that melatonin diminishes nuclear translocation of p65, p50, and p52 subunits of NF-κB. It could thus affect the invasiveness of the tumor through reducing binding of P56 and P52 to the MMP-9 promotor [72].

In gastric adenocarcinoma, melatonin reversed (IL-1β)-induced epithelial-to-mesenchymal transition (EMT). Further evaluations showed increased levels of β-catenin and E-cadherin as well as dimin- ished expression of genes involved in tumor invasiveness including fibronectin, vimentin, Snail, MMP-2 and MMP9. All these changes have been shown to be initiated in response to NF-κB activation that may have been suppressed by melatonin [76,77]. As a transcriptional factor, NF- κB is capable of interacting with COX-2 promotor, which leads to increased tumor invasiveness [49,78]. Melatonin was also shown to disrupt physiological interaction of NF-κB and CCAAT/enhancer bind- ing protein-beta (C/EBPb) resulting in the down regulation of COX-2 and the consequent suppression of tumor invasiveness [79].

Pretreatment of gastric cancer cells with an inhibitor of calpain, a cytosolic calcium-activated protease, reduced the affinity of both NF-κB and C/EBPb to the COX-2 promotors [79]. Similar results were obtained by co-treatment of melatonin and berberine in non-small-cell lung car- cinoma (NSCLC). It was shown that berberine alone had no effects on the binding of p50 NF-κB to the COX-2 promoter, while the addition of melatonin to the treatment regimen inhibited COX-2 protein expression. It was also shown that melatonin had no effects on P50 expression levels. Moreover, it was demonstrated that melatonin induced endoplasmic reticulum stress and enhanced calpain phosphorylation [79]. Melatonin also increased the anti-tumor effects of fisentin, a natural flavonoid, by decreasing the nuclear accumulation of NF-κB and its co activator P-300 [80].In advanced prostate cancer, the anti-proliferative effects of mela- tonin were attributed to the suppression of NF-κB signaling through activating its MLT-1 receptors [81]. In prostate cancer, the androgen receptor splice variant-7 (AR-V7) was found to be over expressed; melatonin inhibited the bidirectional positive association between AR- V7 and NF-κB. Melatonin exerts these beneficial effects via MLT-1 as these actions were reversed by luzindole, a melatonin receptor antagonist [82].

4. Heat shock protein as a key target

Heat shock proteins (HSP) are highly conserved proteins involved in cell survival against lethal conditions [83]. They are categorized into six families based on their molecular weight and are involved in protein transport, translocation and folding [83]. HSP27 is a small HSP pos- sessing a molecular weight of 15–30 kDal, which becomes phosphory- lated by MAPKAP kinases 2 and 3, 90 kDa ribosomal S6 kinase (p90Rsk), Protein kinase C (PKC), protein kinase D (PKD) and PKG that modulate oligomerization along with the chaperon activity of HSP27 [84,85]. HSP27 is highly expressed in many cancers and has shown tumorigenic effects in some studies [86]. HSP27 exerts anti-apoptotic effects through the inhibition of caspase 3 and cytochrome c release, which can induce chemotherapy resistance [87,88]. While melatonin alone had no cyto- toxic effect on ovarian cancer, it did beneficially increase the cytotoxic effects of cisplatin [89]. Melatonin increased the cisplatin induced apoptosis through caspase 3 activation. It was purposed that the com- bination of melatonin and cisplatin had inhibited phosphorylation of ERK and downstream p90RSKs [89]. Previously, the cross talk between p90RSKs and HSP27 had been discovered. Therefore, this effect of melatonin consequently suppresses HSP27 phosphorylation leading to cell sensitization to chemotherapy [89]. Likewise, HSP 90 is highly expressed in malignancies. A multi-chaperon complex containing HSP 90 is involved in malignant cell growth, survival and invasion [90]. HSP90 triggers angiogenesis through regulating hypoxia-inducible fac- tor-1α (HIF-1α) and vascular endothelial growth factor receptor (VEGFR) [90]. It also activates MMP-2, thus facilitating metastasis. Although HSP90 is an abundant chaperon and is promising as a target in cancer treatment, to our understanding no study has been performed to test the potential beneficial role of melatonin on the levels of HSP90.

5. DNA methylation and cancer

Stable epigenetic modifications are the most common molecular al- terations that are detected in most cancers including breast and brain cancers [91]. Two common type of these alterations include demethy- lation and methylation of CpG islands [92,93]. These phenomena are catalyzed by DNA methyl transferases and affect cell proliferation, dif- ferentiation, invasion and apoptosis through gene expression modula- tion. Evaluation of epigenetic alterations through high performance capillary electrophoresis showed that hyper methylation of tumor sup- pressor genes and hypo methylation of pro-metastatic genes occur in malignancies [93]. In addition, epigenetic modulation of microRNA expression is also detected in many malignancies [94]. Thus, pharma- cological targeting of pathologic epigenetic modifications is of great importance. In this regard, DNA methyl transferase inhibitors have passed phase I -III clinical trials [95]. In this context, melatonin and its metabolites have shown promising effects in reversing the pathologic epigenetic modifications through either inhibition of DNA methyl transferase or masking the target sequences [96–98].

Global methylation was diminished in light-at-night (LAN)-exposed mice bearing 4 T1 breast cancer cells [93]. Melatonin leads to altered methylation of 5256 and 6543 CpG islands in a dose-dependent manner. Melatonin has been also shown to induce differential alterations in the methylation status of different genes such that oncogenic genes. These alterations are such that including EGR3 and POU4F2/Brn-3b were hypermethylated while, GPC3, a tumor suppressor gene, was hypo- methylated following melatonin treatment. [99,100]. Hyper- methylation of EGR3 by melatonin was shown to suppress estrogen- mediated invasiveness of breast cancer [101]. Melatonin also alters aromatase expression via inducing epigenetic modifications [102]. Brain tumor stem cells are responsible of multidrug resistance and tumor relapse. Considering the tumor sensitizing effect of melatonin, it was purposed that melatonin could diminish the expression of ABCG2/BCRP at mRNA level, leading to intracellular accumulation of anti-cancer drugs. In fact, melatonin enhanced ABCG2 promotor methylation that was reversed by 5-azacitidine (AZA), a DNA methyl-transferase inhibitor [67,103].

6. Estrogen responsive genes as cancer drug targets

It was demonstrated that the incidence of breast cancer increased in pinealectomized rats [104]. Moreover, proliferation of breast cancer cells was also suppressed by melatonin treatment [21,105]. Thus, not only does the melatonin secreted by pineal gland act as a protective factor against breast cancer development, but also suppresses breast cancer cell invasion and progression [106,107]. In addition, evidence has shown the dependence of melatonin on the presence of estrogen receptors. In fact, it has been proposed that there might be an important cross talk between melatonin signaling and estrogen receptors in es- trogen receptor (ER)+ breast cancer cells [108]. Signals triggered by melatonin involved in the modulation of cell cycle regulatory genes [109]. It is also suggested that these beneficial effects might correlate with the modulatory roles of melatonin in immune system and sexual hormones. It has been shown that circadian melatonin alters 17-beta estradiol secretion [104,110]. Melatonin excretes anti-estrogenic activ- ity in ER+ breast cancer cells. Melatonin not only is capable of inhibiting estrogen binding to ER-alpha receptor, but also inhibits estrogen trans-
activation [111]. It suppresses estrogen responsive genes including BRCA-1, P53, P21 and c-Myc. These effects correlate with the expression of MT1 on cancerous cells. The activation of MT1 leads to the suppres- sion of CREB phosphorylation followed by diminished gene expression of CRE-containing promotors [112]. Due to the presence of cAMP- responsive element (CRE) in the promoter of BRCA-1, its expression was diminished by melatonin. Furthermore, the expressions of P27, P21, P53 and c-Myc were also modulated [113,114].

7. Myc as a cancer drug target

Myc is the most dysregulated oncogene in many malignancies including B cell lymphoma, breast, colon, prostate and lung cancers [115,116]. In vertebrates the MYC family includes c-Myc, MYCN and MYCL1 members [117]. As members of this family are involved in a wide range of signal transduction pathways, they are highly-regulated at gene, mRNA and protein levels [118,119]. MYCs are involved in cellular growth, proliferation, metabolism and pluripotency. Such multi- functionality of the MYC family is mediated by transcriptional and non- transcriptional modifications [120,121]. A combination of physiological concentrations of melatonin and arsenic trioxide showed promising therapeutic effects in breast cancer. It was shown that melatonin co- treatment of MCF-7 cells triggers apoptosis via induction of P53 and P21 expression [122]. P53 downregulates human telomerase reverse transcriptase via Myc suppression [123,124]. Another study showed the altered c-Myc expression represses P53 gene expression, which is due to the presence of c-Myc responsive element in its promotor [125]. Therefore, it can be concluded that there might be a reciprocal associ- ation between c-Myc and P53. Thus, melatonin seems to decrease the transcriptional activity of c-Myc and human telomerase reverse tran- scriptase [112]. Likewise, previous studies showed that in acute pro- myelocytic leukemia (APL), breast and endometrial cancer, the induction of P21 reduced human telomerase reverse transcriptase mRNA expression [126,127].

Cancer stem cells are cornerstones of induction of chemotherapy resistance via massive cross talk with the microenvironment and the consequent genetic alterations [128]. c-Myc is involved in the mainte- nance of pluripotency and self-renewal properties of cancer stem cells [129,130]. In addition to c-Myc, the high expression of nestin in neural stem cells induces invasiveness and stemness of glioma [131,132]. In an in vitro experiment, it was shown that melatonin decreased nestin and c- Myc at mRNA and protein levels via activation of its MT1receptor. The reversal of these observed effects following co-treatment with luzindole confirmed the receptor involvement. Interestingly, it was shown that although c-Myc is located in the nucleus and nestin is distributed in cytoplasm, these two molecules are positive regulators of each other and the small ubiquitin-related modifier-1 (SUMO-1) mediates this cross talk. Melatonin disrupts this crosstalk via the suppression of SUMO-1 expression followed by decreased nuclear translocation of nestin. In fact, melatonin interferes with c-Myc via triggering proteosomal degradation [133].

8. AKT/PKB pathway and cancer

AKT, protein kinase B (PKB), has been widely studied as a key regulator of oncogenesis, angiogenesis, metastasis and chemoresistance [134]. Melatonin diminished the phosphorylation of p85, 110β, PDK1 and AKT in colon cancer, resulting in the reduced proliferation and metastasis of the malignant cells [135]. In NSCLC, co-treatment of melatonin and berberine had no effects on AKT and ERK1/2 levels, while melatonin synergized the anti-tumor actions of berberine by enhancing the inhibitory effect of berberine on AKT and ERK1/2 phos- phorylation [73]. Using the inhibitors of AKT and Mek1/2 (LY29400 and U0126, respectively) gave rise to similar effects on cancer cell growth, indicating that melatonin influences AKT/ERK signaling [73]. Other investigations showed that the suppression of c-jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) activation by melatonin is mediated by AKT modulation [72]. JNK and ERK belong to the MAPK family, involved in cell survival and proliferation [136,137]. The MAPK/NF-κB signaling is abolished by AKT suppression.

Melatonin suppresses MPK-mediated NF-κB activation by decreasing P38 phosphorylation [66]. It was claimed that JNK and ERK activation increases apoptosis [138,139], in pancreatic cancer melatonin enhanced p-JNK and p-ERK, leading to cell death. Activation of MAPK also increased caspase-3 cleavage and the expression of apoptotic proteins [71]. Likewise, in gastric cancer, melatonin at a concentration of 2 nM elevated p38, JNK and ERK phosphorylation [74]. However, treatment of gastric cancer cells with PD98059 (ERK inhibitor), failed to cause alterations in melatonin-induced apoptosis, suggesting that this apoptosis is independent of the ERK pathway. Additional evaluations indicated that P38 and JNK play critical roles in apoptosis induction of melatonin [74]. As discussed previously, melatonin suppressed COX-2 expression. This could further lead to decreased PGE2 levels and down regulation of EGFR, PI3K, and ERK1/2 [140].

9. Role of LncRNAs in cancer

Long non-coding RNAs (LncRNAs) play regulatory roles in various biological processes via modulation of gene expression and protein function [141,142]. They are also involved in effector mechanisms of drugs [143,144] and their dysregulations have been observed in many pathologic conditions [145]. In addition to the well-known anti-cancer effects of melatonin including inhibition of proliferation, migration and invasion, this small indoleamine is capable of diminishing DNA repair capacity of malignant cells, as confirmed by comet assay of melatonin- treated cells. This feature allows melatonin to sensitize malignant cells to chemotherapy and radiotherapy [146,147]. DNA damage repair mechanisms are categorized in two classes including double and single strand DNA repair [148]. Melatonin suppresses homologous recombi- nation DNA repair, which is the major mechanism of double strand DNA damage. The homologous recombination DNA repair is mediated by RAD51 [149,150]. Investigations have shown that melatonin increases the expression of the long noncoding RNA RAD51-AS1, which reduces RAD51 levels through binding to RAD51 mRNA. This complex is simply recognized and degraded by RNAase H [151,152]. In conclusion, the finding that melatonin can sensitize malignant cells to the DNA damage either induced by chemotherapy or radiotherapy by changing the levels of RNA RAD51-AS1 indicates that there might be other LncRNAs, which can be potentially affected by melatonin [146]. Therefore, further studies are required to explore the involvement of other LncRNAs in the anti-cancer effects of melatonin.

10. Cancer targets in angiogenesis and metastasis

New blood vessel formation, known as angiogenesis, is essential for tumor progression through the provision of nutrients and oxygen and removal of wastes. Matrix metalloproteinases (MMPs) and growth fac- tors mainly including epidermal growth factor (EGF), vascular endo- thelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are key endogenous stimulators of angiogenesis [153]. VEGF acts via three types of vascular endothelial growth factor receptors (VEGFRs) that might be either membrane bound or soluble [154]. The binding of growth factors to their receptors leads to the dimerization of these tyrosine kinase receptors and influences auto-phosphorylation cascades. Moreover, endothelial cell proliferation is mediated by the c-Raf-MEK- MAP-kinase pathway, which is activated by PKC following its stimula- tion by VEGFRs [155]. It has been demonstrated that melatonin is capable of diminishing the expression levels of these receptors, specif- ically VEGFR-2, the most effective receptor in angiogenesis induction. [156]. Melatonin also exerts its anti-angiogenic effects through reducing VEGF mRNA levels in a dose-dependent manner [157]. Surprisingly, VEGF levels may not always be suppressed by melatonin. Further in- vestigations have revealed that melatonin might alter mRNA splicing of VEGFs and VEGF-2, which has been purposed based on the observations of increased VEGFs and VEGFR-2 levels in mice bearing human prostate cancer cells [158]. In a study on breast cancer it was shown that mela- tonin induces its post-transcriptional gene regulatory effects via increasing the levels of miR-152-3p, which targets several genes including IGF-1R, Hypoxia-inducible factor 1 (HIF-1α) and VEGF [159]. VEGF transcription is regulated by HIF-1 and STAT-3 transcription factors [160].

Melatonin interferes with hypoxia-induced angiogenesis through diminishing HIF-1α, one of the two subunits of the HIF-1 heterodimer [157]. In addition, melatonin increased HIF-1α degradation by enhancing the activity of prolyl-4-hydroxylases (PHDs) [161]. PHDs trigger site specific hydroxylation of HIF-1α followed by its poly- ubiquitination and the consequent proteasomal degradation [162]. Restoration of PHD activity might be attributed to the antioxidant properties of melatonin that preserves the active site ferrous ion from oxidation [161,163]. Melatonin may also affect nuclear translocation of HIF-1α and diminish STAT-3 phosphorylation. This further prevents the activation of VEGF promotor via diminished binding of CBP/p300 coactivator to these transcription factors [160].

Melatonin reverses the high viability and angiogenesis capability of human umbilical vein endothelial cells (HUVEC) through affecting the HIF-1α/VEGF/ROS axis, particularly in combination with KC7F2 (HIF- 1α translation inhibitor) [164]. Likewise, melatonin treatment in pros- tate cancer blocks sphingosine kinase 1 (SPHK1) and ROS generation,leading to the inactivation of HIF-1α [165]. An in vivo study on gastric cancer showed the involvement of the nuclear receptor RZR/RORγ in the reduction of HIF-1α levels [166]. In agreement with this, using specific inhibitors of melatonin membrane receptors caused no alter- ation in phosphorylation status of VEGFR-2. In contrast, in one inves- tigation in mice bearing serous papillary ovarian carcinoma showed the anti-angiogenesis effect of melatonin is mediated through MLT-1 [167]. Addition of melatonin to the HUVEC and MCF-7 co-culture decreased angiogenic factors including angiopoietin-1(ANG-1), angiopoietin-2 (ANG-2) and VEGF at both mRNA and protein levels. The balance be- tween ANG-1 and ANG-2 is involved in vascular homeostasis by acting on the Tie2, a receptor tyrosine kinase, signaling pathway. Melatonin has been also shown to induce the overexpression of Tie2, leading to vessel stabilization and dampened vessel sensitivity to pro-angiogenic factors [168].

Melatonin reduces the invasiveness of tumors through affecting adherent and tight junctions. It modulates the cross talk between cells and the extra cellular matrix mainly via expression regulation of integ- rins [169,170]. It has been shown that decreased E-cadherin is involved in early steps of metastasis that are reversed by melatonin. Clinical data from gastric cancer patients has shown a direct association between metastasis and CCAAT/enhancer binding protein-beta (C/EBPb) over- expression. Further evaluations showed that melatonin could decrease macro-metastasis, which was associated with C/EBPb inhibition by gene silencing. It was then revealed that melatonin regulates C/EBPb expression through E-I/II. In fact, melatonin suppresses peritoneal dissemination of cancer cells via regulation the C/EBPb–E-cadherin axis [79].

An important target pathway of melatonin to repress metastasis is occludin/PI3K [171,172]. In addition, melatonin may exert its anti- metastatic effects by inhibiting the remodeling of extracellular matrix (ECM) and the degradation of its main constituent including collagen, native type IV collagen, type V/XI collagen and elastin by matrix met- alloproteases [173,174].

Another important effect of melatonin as an anti-metastatic agent is the suppression of epithelial-mesenchymal transition mostly via the regulation of several transcription factors including Snail, Slug, Twist, and Zeb by NF-κB [79,175]. It also impacts microtubule and microfila- ment reorganization to inhibit metastasis [176]. In a related study, melatonin synergizes with the antitumor effect of berberine in lung cancer. Decreased levels of MMP9 and β-catein confirmed the anti- metastatic effect of melatonin [73]. Although, treatment of Caki-1 and Achn cells and renal cell carcinoma cells with melatonin downregulated MMP-9, it caused no alteration in MMP-2 expression. Human protease array showed that melatonin could decrease the levels of urokinase plasminogen activator (uPA), MMP-2, MMP-9, MMP-3, ADAMTS-1, cathepsin C and presenilin-1 [72]. As previously discussed, regulation of NF-κB signaling is involved in MMP transcription. It was shown that MMP-9 transcription was suppressed by melatonin through the modu- lation of AKT-Erk/JNK and the downstream NF-κB [177].

11. Clinical trials on the anti-cancer effects of melatonin

Various clinical trials have been carried out and many are under way to examine the beneficial effects of melatonin in various cancers. The results from the previous trials were indicative of the protective effects of melatonin against various cancers and its usefulness in modulating the side effects of chemotherapy and radiotherapy, in certain cases, increasing the effectiveness of drugs and improving the patients` quality of life.
In a clinical trial of patients with NSCLC, Nora et al. combined melatonin with somatostatin, vitamin D, retinoids and cyclophospha- mide. The results showed an improvement of the respiratory as well as other disease-related symptoms in the poor prognosis patients [178]. In another similar study, melatonin in combination with cisplatin and etoposide was able to increase the 5-year survival rate in patients with NSCLC, increasing the effectiveness of the chemotherapy regimen [179]. On the contrary, in another similar study, although the use of melatonin in NSCLC patients improved the quality of life of the patients, it had no protective effects against the chemotherapy side effects [180]. This is while, a combination of melatonin with Campothecin-11, a drug used in metastatic colon cancer, could increase chemotherapy effectiveness [181]. Integrating melatonin in a cisplatin-based standard regimen was has been shown to be able to reduce anemia, a common side effect of cisplatin, and enhance the efficacy of chemotherapy [182].

In another effort by Persson et al., the efficacy of melatonin in attenuating the side effects of chemotherapy in patients with gastroin- testinal cancer was investigated. Based on the findings, melatonin could stabilize body weight in the studied subjects, while it had no effect on cachexia [183]. Lissoni et al. evaluated the effects of melatonin and interleukin-2 (IL-2) on radiotherapy-induced lymphocytopenia in pa- tients with colorectal cancer and adenocarcinoma of the uterine cervix. Contrary to the beneficial anticancer effects observed in many studies, in a study by …., melatonin had no positive effects on lymphocytopenia and the effectiveness of radiotherapy [184]. This is while melatonin has been found to be capable of hindering the radiotherapy-induced neu- tropenia and reticulocytopenia in rectal cancer patients [185]. Another finding supporting the beneficial radioprotective effects melatonin was the results of a study in which melatonin co-administration to head and neck cancer patients could not only inhibit the decrease in total anti- oxidant capacity of the patients, but also improve pain and mucositis, the most common complications in these patients [186]. The neuro- protective effects of melatonin have also been investigated in patients with breast cancer. Melatonin was able to improve depressive symptoms and sleep quality [187].

12. Conclusion

Melatonin has been identified as a safe and effective agent against many types of cancers. This indoleamine targets a wide range of medi- ators involved in cancer metabolism at both transcriptional and post transcriptional levels. Although, there are controversies regarding the precise mechanisms of action and the responsible mediators, which might be due to differences in the study design, in almost all studies melatonin has been shown to interfere with tumor progression. Mela- tonin could either directly affect pathologic signaling pathways mostly mediated by ERK, AKT and JNK or may indirectly modulate them via affecting their upstream processes. Melatonin can also beneficially induce genetic alterations including epigenetic modifications, suppres- sion of oncogenes, regulation of LncRNAs and microRNAs and the in- duction of changes in the expression of transcription factors. Taken together, melatonin could decrease p-IκBα and p-IKKβ leading to NF-κB activation, which sensitizes malignant cells to the anti-tumor drugs. Moreover, melatonin exerts its anticancer effects including inhibition of proliferation, migration and invasion through the reduction of DNA repair capacity, resulting in the sensitization of malignant cells to radiotherapy and chemotherapy. Alterations in the viability and angiogenesis capability of endothelial cells have also been shown to be induced by melatonin via ROS generation and inactivation of HIF-1α. Based on our understanding of targets in cancer therapy, we strongly recommend considering the use of melatonin as a potential adjuvant therapy in the treatment of many cancers. Since the functional mecha- nisms of melatonin are highly dependent on the cancer type, more clinical trials on the anti-cancer effects of melatonin are warranted to elucidate the effects of melatonin in various cancers. Considering the occasional controversial results obtained in different clinical trials on patients with the same cancer types, it seems to be a priority to consider the technical and methodological differences between these studies to elucidate the reasons behind such controversies.

Declaration of competing interest

The authors have no conflict of interests to declare.

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