Melatonin and its ubiquitous anticancer effects

Sankha Bhattacharya1 · Krishna Kumar Patel1 · Deepa Dehari1 · Ashish Kumar Agrawal1 · Sanjay Singh1,2

Received: 11 June 2019 / Accepted: 17 August 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Melatonin (N-acetyl-5-methoxy-tryptamine), which is generally considered as pleiotropic and multitasking molecule, secretes from pineal gland at night under normal light or dark conditions. Apart from circadian regulations, Melatonin also has anti- oxidant, anti-ageing, immunomodulation and anticancer properties. From the epidemiological research, it was postulated that Melatonin has significant apoptotic, angiogenic, oncostatic and anti-proliferative effects on various oncological cells. In this review, the underlying anticancer mechanisms of Melatonin such as stimulation of apoptosis, Melatonin receptors (MT1 and MT2) stimulation, paro-survival signal regulation, the hindering of angiogenesis, epigenetic alteration and metastasis have been discussed with recent findings. The Melatonin utilization as an adjuvant with chemotherapeutic drugs for the reinforcement of therapeutic effects was also discussed. This review precisely emphasizes the anticancer effect of Melatonin on various cancer cells. This review exemplifies the epidemiology and anticancer efficiency of Melatonin with prior atten- tion to the mechanisms of actions.

Keywords Melatonin · Non-small-cell lung cancer · Apoptosis · Angiogenesis · APUD system
Abbreviations
13-HODE 13-Hydroxy octadecadienoic acid
AANAT Arylalkiamin N-acetyltransferase
ACS American Cancer Society
AGS Aicardi–Goutières syndrome
aMT6s 6-Sulphatoxymelatonin
AKt Protein kinase B
APUD Amine precursor uptake and decarboxyla- tion system
AR Androgen receptor
CAMKIIα Calcium/calmodulin-dependent protein kinase type II alpha chain
cAMP Cyclic adenosine monophosphate
E2-ER
EGFR
ERE
ERα
ERα
ERK
GC
GCSLC
GHFs
HDAC4
HGF
HOCl.
hTERT
Estradiol
Epidermal growth factor Estrogen response element Estrogenic receptor Estrogenic receptor
Extracellular signal-regulated kinase Gastric cancer
Glioblastoma cancer stem-like cells
Growth hormone-dependent growth factors Histone deacetylase 4
Hepatocyte growth factor Hypochlorous acid
Telomerase reverse transcriptase

CCl3O2 CDK1 CDK4 COX-2 DNES
Trichloromethylperoxyl Cyclin-dependent kinase 1 Cyclin-dependent kinase 4 Cyclooxygenase-2
The diffusive neuro-endocrine system
IGBBP-3 IGF1
IGF-1 IUPHAR JNK
Insulin-like growth factor-binding protein 3 Insulin-like growth factor 1
Like growth factor-1
Union of Basic and Clinical Pharmacology c-Jun N-terminal kinase

LAN Light at night
MAPKs Microtubule-associated protein kinase

*

[email protected]
MFC
MLT
Murine for gastric carcinoma Melatonin

1Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh 221005, India
2Babasaheb Bhimrao Ambedkar University (BBAU), Lucknow, Uttar Pradesh 226025, India
MTNR1a Melatonin receptor 1a
MTNR1B Melatonin receptor 1B variant B
MTNR1b Melatonin receptor 1b
Vol.:(0123456789)
NF-kB

NSCLC
OC
OPG

Nuclear factor kappa-light-chain-enhancer of activated B cells
Non-small-cell lung cancer Ovarian cancer Osteoprotegerin

hormone can be estimated by measuring saliva, urine sul- phatoxymelatonin and plasma [8]. Surprisingly, Melatonin level during daytime and elevates at night. It is astonish- ingly reported that elevated Melatonin level in nighttime send a signal to body’s organs and cells to arrange homeo-

p27 (Kip1) Cyclin-dependent kinase inhibitor
PCa Prostate cancer cells
PDGF Platelet derived growth factors
PrPc Prion protein
PSQI Pittsburgh sleep quality index
QR2 Quinone reductase 2
RNS Reactive nitrogen species
ROR Related orphan receptor
ROS Reactive oxygen species
RZR/RORα Retinoic acid-related orphan nuclear hor- mone receptor
SCN Suprachiasmatic nucleus region
SRB Sulforhodamine B A
TGF Transforming Growth factor
TNF-α Tumour necrosis factor alpha
VDR Vitamin D receptor
VEGF Vascular endothelial growth factor
WHO World Health Organization
Introduction

The pineal gland, which is located on the third ventricle of the brain, is responsible for synthesizing Melatonin (N-acetyl-methoxy-tryptamin) (MLT) hormone [1]. Mela- tonin has higher spreadability in intracellular and extracel- lular cells due to its chemical structure and lower molecular weight (278 kDa) [2]. Apart from the brain, Melatonin is also synthesized in lymphocytes, bone marrow, eyes and gastrointestinal tract. The very interesting fact of Melatonin is, it lightens the frog skin by sinking melanophores, which governed the naming of this hormone as Melatonin [3]. The biosynthesis and metabolism of Melatonin have been sum- marised in Fig. 1. This methoxyindole synthesized endo- crine hormone MLT regulates human chronobiological func- tions like circadian rhythms [4]. The suprachiasmatic nuclei (SCN) located in hypothalamus is responsible for maintain- ing physiological circadian rhythm. The SCN stimulates Melatonin to activate night-state physiological functions like sleep/weak blood pressure and metabolism [5]. Fundamen- tally, circadian rhythm is an internal biological clock, which oversees different trainable oscillation within a 24-h period in the human body [6].The primary metabolite 6-sulphatox- ymelatonin (aMT6s) of endogenous melatonin is helping to regulate this rhythm. Apart from the central circadian clock, Melatonin also modulates peripheral oscillation in organs and tissues [7], which makes Melatonin a best marker of circadian rhythms. Usually, the nyctohemeral rhythm of this
static metabolic rhythms [9]. Therefore, light at night (LAN) could drastically alter Melatonin production and circadian rhythms [8, 9]. According to the American Cancer Soci- ety (ACS), fluctuation of Melatonin level in body enhances antioxidant effects and stimulate white blood cells which leads to the progression and development of cancers [10]. As per the World Health Organization (WHO), 9.6 Million cancer deaths had been reported during 2018 [11]. Due to cancer, the morbidity and mortality rate increases up to ten- fold worldwide recently. The most alarming cancer is breast cancer with 268,670 new registered cases in the United State of America (USA) in 2018. Nevertheless, prostate cancer and lung cancer also seems to be a big concern for scientists [12]. As far as Melatonin is a concern, it is capable of drasti- cally altering estrogenic mediated cellular pathways, which leads to the reduction of estrogenic stimulation of cells and capable to produce the good oncostatic effect [13]. Mela- tonin also has good anti-apoptotic and antioxidant property by annihilating toxic oxygen derivatives like reactive oxygen species (ROS) [14]. Apart from ROS, Melatonin also oblit- erates reactive nitrogen species (RNS) by which it could cleave oxidative and nitrosative damage of macromolecules of all compartments of the cell. Melatonin also plays a vital role to decimate ROS and RNS levels in mammalian gam- etes and embryos which helps to reduce peroxide concen- trations and DNA damage, and therefore the viability of germ and embryonic cells is palpable [15]. In this review the biosynthesis and metabolism of Melatonin has also been summarized along with anticancer efects, as per the recent discovery and findings [16].
Antioxidant property of Melatonin buzzes anticancer effects

During 1991, Ianas and colleagues did strong revelation by suggesting that Melatonin could have good free radi- cal scavenger property [17]. Two years later (1993), Tan and co-workers proved that Melatonin has good scavenging property for–OH group. As already mentioned –OH group is responsible for cellular toxicity, so the Tryptophan deriv- ative, Melatonin, proved to have protective action against oxidative attack [18]. Tan et al. findings were approved by confirming the elimination of –OH group in electron spin resonance spectroscopy (ESR) study of Melatonin [19]. Basically, Melatonin generates antioxidant action by com- bining with luminol and H2O2, the resultant chemilumines- cence act as an index of free radical production. Modern

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
Fig. 1 Melatonin biosynthesis and metabolism process
research has also suggested that Melatonin also remove free radicals of trichloromethylperoxyl (CCl3O2) and hypochlo- rous acid (HOCl) [20]. Melatonin suppresses pro-oxidant enzymes and upregulates antioxidant enzymes and thus it produces good cardioprotective effects. Due to the presence of lipophilic property in Melatonin (LogP1.42), it can easily penetrate in morphophysiological barriers and subcellular compartments of cardiac cells, which result in the reduction of oxidative stress. Rodriguez et al. reported the significant role of Melatonin in boosting actions of antioxidant enzymes and increasing cellular mRNA levels. Melatonin could pos- sibly stimulate superoxide dismutase and glutathione per- oxidase enzymes under elevated oxidative stressful condi- tion [21]. Due to the good antioxidant effect of Melatonin, it can also act as a cell protector and potential disease
prevailing agent. As far as anticancer effects of Melatonin are concerned, from the last decade meta-analysis, it was confirmed that alteration of circadian rhythm can kick can- cer in humans. The antioxidant effect, estrogenic synthesis, anti-angiogenesis, activation of body immune system and epigenetic influences could effectively vandalize cancer pro- liferative cells. Moreover, the Melatonin and its metabolites like cyclic-3-hydroxymelatonin (cyclic-3OHM), 6-hydrox- ymelatonin (6-OHmel), N (1)-acetyl-5-methoxykynuramine (AMK) shows phenomenal antioxidant effects by scavenging reactive oxygen species (ROS) and radical reactants [22]. This chemical condition kindles the countenance of major anti-oxidative enzymes like glutathione peroxidase (GPx) and catalase (CAT), which are partially agonistic for Mela- tonin anticancer properties. Taxanes, paclitaxel (PAC) and

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig. 2 The various mechanisms involved in organized anticancer effects by Melatonin
docetaxel (DOC) represent an important class of anti-tumour agents and have proved to be fundamental in the treatment of advanced and early-stage ovarian, breast, lung, pancreatic and other cancers [23].
Various mechanisms of action and pathways of Melatonin as an anticancer agent

Melatonin has versatility in influencing numerous physio- logical processes. There are plenty of articles suggesting that Melatonin has staggering in vitro effect on various tumour cell lines and their apoptosis. However, there is no uniform consent on why and how Melatonin behaves differently on various oncogenic molecules and culture medium conditions [24]. Melatonin downregulates following growth factors: prolactin-insulin-like growth factor-1(IGF-1), growth hor- mone-dependent growth factors (GHFs), Epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), transforming growth factor (TGF), platelet derived growth factors (PDGF), by which indirectly it hinders the negative tendency of healthy cells to become cancerous [25]. Melatonin also upregulates apopto- sis in which healthy cells replace tumorous cells, it stimu- lates mitochondrial-dependent activation route of
cysteine-aspartase, which irreversibly propagate malignant cell death [26]. As per Union of Basic and Clinical Pharma- cology (IUPHAR), different forms of higher and lower affin- ity Melatonin receptors were identified (MT1 and MT2), which interacts with intercellular proteins like ROR, RZR, calmodulin etc. MT1 and MT2 were formally known as Mel1a and Mel1b. The MT1 and MT2 were enlisted in the family of guanidine triphosphate-binding proteins and share plenty of their amino acid sequences [27]. As far as the pro- liferation of tumour cells were a concern, linoleic acid plays a key role. It is used in the biosynthesis of prostaglandin and cell membrane. During cell narcosis, linoleic acid in the presence of 15-lipoxygenase oxidized to 13-hydroxy octa- decadienoic acid (13-HODE), which act as an energy source for tumour signalling molecules. Since Both MLT1 and MLT2 are involved in adenyl cyclase and cyclic AMP (cAMP) inhibition, decrease cAMP production reduces the uptake of linoleic acid [28]. The inhibition of linolenic acid uptake by cancerous cells is due to the Melatonin effective role [29], which tends to produce anti-proliferative effects. Some other studies suggesting the presence of tried proto- type of Melatonin receptor, which is known as X-linked orphan G-protein coupled receptor (GPR50) [30]. However, this receptor function is unclear. Presumptively, it has a key role in hypothalamic functions and interaction of the

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
Fig. 3 The multimodal mechanism of Melatonin to tackle gastric cancer
regulatory protein with MT1 receptor. Recently, as per mass spectroscopy and enzymatic data analysis, the chemical entity called Quinone Reductase 2 (QR2) has identified with the tendencies like Melatonin [31] and named as MT3 recep- tor. The various mechanisms involved in inhibiting cancer- ous cells by Melatonin were: the antioxidant effect, funda- mental regulation of estrogenic receptor expression, depletion of telomerase activity, apoptosis and differentia- tion, anti-angiogenesis, epigenetic alteration, cell cycle arrest, energy metabolism, post-survival (Fig. 2) [32]. MT1 receptor consists of 351 amino acids. It encodes in human chromosome #4. MT1 receptor vastly available in human skin and initiates adenylate cyclase inhibition by grafting with different G-proteins [33]. During ageing and Alzhei- mer’s disease, MT1 receptor expression decreases in coGr- tex and suprachiasmatic nucleus (SCN) region [34]. On the other hand, MT2 receptor comprising of 363 amino acids and encoded in human chromosome #11. MT2 receptor also inhibits adenylate cyclase like MT1 receptor and cleave the
production of cyclic AMP (cAMP), in addition to that, MT2 receptor also inhibits the soluble guanylyl cyclase pathway. The MT3 receptor is located in muscle, kidney, liver, intes- tine, heart, brown flat tissue. MT3 helps to reduce oxidative stress by inhibiting electron transfer reactions of quinones [35]. As per the previous report, Melatonin could also binds with Retinoic acid-related orphan nuclear hormone receptor (RZR/RORα) [36]. As far as the anti-carcinogenic activity of Melatonin were concerned, free radical scavenging prop- erties and antioxidant activity plays a key role [37]. Mela- tonin reduces the expression of the estrogenic receptor (ERα) and restrains the binding of estradiol (E2-ER) com- plex to the estrogen response element (ERE) on DNA [38]. In estrogen signalling pathway, Melatonin also deactivate calmodulin which helps to initiate anticancer activity [39]. Melatonin also has telomerase activity (telomerase are the enzyme maid of RNA and Protein which enlarge chromo- somes by adding TTAGGG sequences to the end of existing chromosomes) which begin pro-apoptosis effects on tumour
cells [40]. As per Guerrero et al. study, Melatonin could influence specific and non-specific immunity parameters [41]. It could regulate the production of cytokines and act as an immune enhancer. Some lymphoid organs, such as bone marrow, thymus, lymphocytes, help in synthesizing Mela- tonin. Melatonin directly binds with membrane receptors and nuclear receptors of killer cells, leucocytes, monocytes, interleukins (IL-2, IL-6, IL-12), tumour necrosis factor alpha (TNF-α) and interferon–gamma, to produce the anti- cancer effect [42]. The nuclear receptors have significant structural similarities with the retinoid receptors (ROS and RZR) and vitamin D receptor (VDR). Recent studies on Melatonin cytocellular actions revealed that Melatonin act- ing mainly on phosphor esters of adenosine and some signal transduction systems such as inhibition of Ca2+ mobiliza- tion, hampering the arachidonic acid release, action of pro- tein kinase C, protein C inhibition of adenyl cyclase and the opening of potassium channels [43]. As per Sancez-Barcelo et al. observation, Melatonin upregulate p21/WAF1 and p53 suppressor genes by faltering the progression cycle of tumour cells. In this study, it was also observed that in physi- ological condition, Melatonin reduces the viability of tumour cells within 48 h of administration [44]. Another possible mechanism of Melatonin is inhibition of the expres- sion of HIF-l alpha protein and punishing hypoxia in cancer- ous cells by downregulating vascular endothelial growth factor (VEGF) [45]. Not only in epithelial and endothelial level restricts Melatonin anticancer effect but this molecule has bone protective effect as well. Future holds much antici- patory researches in osteosarcoma treatment through Mela- tonin. In one specific research, it was found that osteosar- coma cells have maximum MT1-mRNA expression and lower OPG-mRNA level [46]. However, normal human osteoblasts and bone marrow cell lines had higher OPG- mRNA level and lower MT1-mRNA expression. These results were significantly underlining the indispensable role of the MT1 receptor in bone oncological research. Melatonin downregulate the enzyme expression of D1, CDK4, cyclin B1 and CDK1 in dose-dependent and time-dependent man- ner to inhibit the effect of MG-63 osteosarcoma cell line [47]. Apart from the receptor pathway, Melatonin also could exert an anticancer effect by various complex mechanisms of action which we have mentioned earlier. As per Sánchez et al. study, Melatonin could control intercellular redox state to produce anti-proliferation effect. The anti-proliferation effect of Melatonin depends upon depletion of intercellular reactive species (ROS) and an increase of intercellular glu- tathione and GSH levels. However, cell death can be acceler- ated by induction of hydrogen peroxide. Hence, increase intercellular redox level motivates Melatonin to produce the anticancer effect. The proper enzyme activation is also a critical factor to differentiate in several cancer cell lines. In antiblastic therapy and tumour etiopathogenesis, Melatonin

enhances the Amine Precursor Uptake and Decarboxylation system (APUD) to channelize anticancer activity [48]. The Diffusive Neuro-Endocrine System (DNES) produced bio- logical active substances like Somatostatin, Glucagon, Gas- trin, Insulin, Serotonin and Melatonin has a significant role in various onset and stages of proliferation [49]. While in terminal stages, the decrease in the number of these cells increase the cancer proliferation. The anticancer activity of Melatonin was not limited within the aforementioned mech- anisms and pathways. Nevertheless, more research needs to be warranted to distinguish between the complex mecha- nisms and selective pathways of Melatonin-induced in anti- cancer studies.
Versatile usage of Melatonin in oncological research

There is plenty of epidemiological and clinical research which supports a protective role of Melatonin in cancer treatment. Most of the Melatonin dependent cancer research was subjected to find the relationship between Melatonin and endocrine system. The alteration of Melatonin level in endocrine system can lead to harvest mammary tumours, cervical uterine, breast and prostate cancer. Some studies also suggest a contrary relationship of circadian Melatonin and breast cancer cells. As per the previous report, artificial light exposure and sleeping time alteration during the night could affect endogenous Melatonin levels which increase the risk of breast cancer [50]. In another cubic spline model study, it was concluded that the relative risk (RR) of breast cancer is predominant with 95% confidence interval (CI) for the subjects who were exposed to higher light at night (LAN) (CI 1.11–1.23) as compared to the subjects who were exposed in ambient LAN (Cl 0.78–1.07, RR 0.91). Ulti- mately, 14% lower risk of cancer was recorded in ambient LAN exposed subjects with 15 ng/mg elevation of creatinine in urine [50]. As per the previous study in females, serum Melatonin levels ≤ 39.5 pg/ml indicates 15 times higher risk of breast cancer than the females with > 39.5 pg/ml. Furthermore, it was also witnessed that, the G allele a GC genotype of ‘MTNR1B gene rs#10830963 polymorphism’ is responsible for increasing breast tumour volume [51]. Deming et al. discussed anti-proliferative effect of Mela- tonin by triggering estrogen pathway [52]. Specifically, three genes, arylalkylamine N-acetyltransferase (AANAT), Melatonin receptor 1a (MTNR1a) and Melatonin receptor 1b (MTNR1b) are highly responsible for posterior effects of Melatonin. It has been postulated that genetic variation within these genes could manipulate protein productions. As a conclusive statement genetic variation of MTNR1a and MTNR1b was highly responsible for producing cancerous cells in the breast in menopausal females. In another study
irregular urinary excretion of Melatonin was found to be an indication for breast cancer [53]. From the five prospective case-controlled study, it was identified that higher levels of 6-sulfatoxymelatonin (aMT6s) in urine could exhibit a lower risk of breast cancer. However, the results may go inappro- priate due to the differences in genetic makeup and different environmental factors.

Prostate cancer

To study the effect of Melatonin in men physiology, Tam et al. demonstrated the Melatonin annihilating effect on LNCaP and VCaP prostate cancer cells by activating MT1 receptor medicated anti-proliferative signalling pathway [54]. Nevertheless, Melatonin has also shown to decrease androgen/AR-mediated transactivation of the prostate spe- cific antigen promoter in the prostate in the epithelial cell lines, by which it downregulates AR signalling and upregu- late Multifunctional Cyclin-Dependent Kinase Inhibitor (p27 (Kip1)), which ultimately leads to anti-proliferative action against prostate cancer cell lines. In the similar direc- tion, Shiu et al. studied the effect of MI1 receptor medi- ated anti-proliferative signalling mechanism on androgen receptor (AR)-positive prostate epithelial cells [55]. The results stipulate that inhibition of active NF-κB (protein complex that controls cytokine production, cell survival and transcription of DNA) by Melatonin receptor (MT1), leads to transcriptional upregulation of p27 (Kip1) [56]. In another investigation, Sigurdardottir et al. performed case cohort study of 928 Icelandic men with no prostate cancer complications. As per this study men with lower 6-sulfatox- ymelatonin (aMT6s) in urine (hazard ratio: 4.04; 95% confi- dence interval 1.26–12.98) have a subsequent higher risk of prostate cancer (PCa) [57]. In another study, Shu-Yu et al. performed a case-controlled experiment on 120 newly diag- nosed prostate cancer patients with 240 age-match controls from January 2011 to April 2014 [58]. The urine samples of these patients were compared with patients who are having lower urinary Melatonin Sulphate. The results suggested that those patients who had above the median level of Melatonin in urine had less susceptibility for prostate cancer. In most recent study Calastretti et al. proved that UCM 1037, a newly synthesized melatonin analogue, has a very prominent anti- cancer effect against prostate cancer cells [59]. The dose- and time-dependent UCM 1037 anti-proliferative activity was measured against 22Rv1 and LNCaP androgen-sensitive prostrate cell lines. Higher cytotoxicity in prostate cancer- ous cells was measured using cytometric studies. However, UCM 1037 cytotoxicity effects were less recorded in andro- gen-insensitive PC3 and DU145 cells.

Ovarian cancer

The recent pharmacological and molecular biological studies indicate that Melatonin has remarkable metastatic and anti- proliferative action against ovarian cancer cells. Melatonin shows effective action against ovarian cancer cells after acti- vation of the M1 receptor. This activation facilitates inhibi- tion of cAMP and reduction of MAPKs, protein kinase A and C. This inhibition and reduction can downregulate the genes involved in metastasis, proliferation and angiogenesis. Mostly due to these actions, MT1 has higher expression in normal ovarian IOSE 364 cells as compared to ovarian can- cerous cells like SK-OV-3 and OVCAR-3. In one cognitive study on MT1 expression in ovarian cancer cells, Karolina Jablonska et al. studied MT1 expression in ovarian cancer (OC) cells to correlate with pathological and clinical data [60]. Using western blot and immunofluorescence tech- niques, ovarian cancer cell lines SK-OV-3, OVCAR-3 and normal ovarian epithelial IOSE 364 cells were examined to identify M1 expression at protein level. Using cytoplas- mic membrane (MT1CM) and membrane (MT1M) reac- tions the expression of MT1 was observed which revealed limited development of MT1 in ovarian cancer (OC) cells. Similarly, Ching-Ju et al. studied the effect of Melatonin in ovarian cancer cell lines (PA-1) [61]. The results sug- gested that downregulation of Cyclin-dependent kinase 2 and 4 is due to the accumulation of Melatonin treated cells in a growth phase which upregulate the anti-tumour activity of Melatonin. A recent report studied the synergistic anti- cancer effect of Cisplatin and Melatonin in ovarian cancer cell lines (IOSE 364, SK-OV-3 and OVCAR-3) [62]. The viability of the cells was examined by ingesting different concentration of Cisplatin and Melatonin to cancerous cell lines. The investigation was done using Sulforhodamine B (SRB) assay method.
Glioblastoma

The endocrine Melatonin has effective anti-glioblastoma activities as well. But very few researches have been car- ried out in this direction. In one specific research conducted by Kyunghee University, Seoul, the Republic of Korea, Hyemin Lee et al. found that Melatonin has the credibil- ity to decrease the sphere formation of Glioblastoma can- cer stem-like cells (GCSLC) and reduces the virulence of c-Myc genes. From the Western blotting and chip assay, they witnessed vanquished expression of H3K79me3 and H3K79me3 cells around the c-Myc promoter region. Dis- tinguishably, Melatonin disseminates the expression of sev- eral stemness markers like nestin in GCSLC [63]. In another study, Zheng et al. observed that the Glioblastoma stem-like cell (GSCs), which is responsible for glioma growth, gets
inhibited and loses its self–renewal ability in the presence of Melatonin. The authors also identified EZH2-NOTCHI signalling pathway was responsible for melatonin effect on Glioblastoma stem-like cells (GSCs) [64].

Colorectal cancer

Melatonin can also play a vital role in depleting colorectal cancer in elderly patients. According to the American Can- cer Society estimation, one in twenty-one men and one in twenty-three women in the United State are prone to colorec- tal cancer during their life time. Colorectal cancer claimed the second leading cause of cancer death and third for men. The malignant type of colorectal cancer can spread across the other body parts as well. In several studies, it has been identified that, Melatonin has a significant role in eradicat- ing colorectal cancer. Hong et al. studied the effect of 10 µM Melatonin induced in HCT 116 human colorectal adenocar- cinoma cells and determined depletion of plasma membrane Melatonin in time-dependent manner. The outcomes of this research indicated that 10 µM Melatonin activate cell death programmes and initiate a G1-Phase arrest [65]. In another study, Wei et al. witnessed Melatonin-induced apoptosis in colorectal LoVo cancerous cells through dephosphoryla- tion and nuclear import of histone deacetylase 4 (HDAC4). This Melatonin dependent apoptosis was largely rely on H3 deacetylation, which ultimately leads to inactivation of Calcium/calmodulin-dependent protein kinase type II alpha chain (CAMKIIα) [66]. In most recent study Yun et al. wit- nessed Melatonin accelerates apoptosis in colorectal cancer. Melatonin could supress PrPc and significantly reduces the production of PINK1 levels which results in superoxide pro- duction in mitochondria. The si-PRNP-transfected colorectal cancerous cells treatment with Melatonin promotes the pro- duction of intercellular superoxide and endoplasmic reticu- lum stress and apoptosis. Melatonin has a good inhibitory effect on cellular prion protein (PrPc). Most recently Jun Hee Lee et al. study abhorrent that, Melatonin and Oxaliplatin inhibited PrPc, can increase endothermic reticulum stress and strengthen apoptosis of SNU-C5/Oxal-R cells. Which means PrPc could be the key factor in oxaliplatin resistance of colorectal cancer cells. Altogether, Melatonin could be a new alluring therapy for colorectal cancer. Melatonin not only regulates carcinogenicity but also restrict the develop- ment and progression of colorectal cancer [67]. There are many underlying signalling pathways like CaMKII, et-1, Nrf2 which regulates Melatonin action against colorectal cancer proliferation [68].

Lung cancer

Melatonin can also play an indispensable role in lung can- cer eradication. According to the American Cancer Society

(ACS), lung cancer is the second most common cancer in both the gender. As per ACS almost 14% new lung cancer patients were recorded in the United State in the year 2018 [69]. About 154,050 deaths from lung cancer (83,550 in men and 70,500 in women) were also been recorded. Non-Small- Cell Lung Cancer (NSCLC) is a most deadly form of lung cancer. From the literature survey, it has been postulated that, NSCLC incidence increases when normal Melatonin rhythm disrupted. Several report suggest that Melatonin could enhance the effect of radiotherapy and anticancer drugs [70]. As per Yun et al. findings, Melatonin can act as a chemotherapeutic agent by sensitizing H1975 non-small-cell lung cancer (NSCLC) which demolishes T790M-targeted epidermal growth factor receptor mutation [71]. As per Lu et al. study, Melatonin could enhance berberine-mediated inhibition of telomerase reverse transcriptase (hTERT) by down rate the projections of AP-2β and it’s binding on hTERT promoter. Melatonin could also inhibit the nuclear translocator of NF-kB and its binding capability on cycloox- ygenase 2 (COX-2). The investigation of this research also reviled that, Melatonin increases the berberine-mediated inhibition of COX-2, phosphorylated Akt and ERK. Since, Melatonin could inhibits the AP-2β/hTERT, NF-κB/COX-2 and Akt/ERK signalling pathways, therefore Melatonin could enhanced the anti-lung cancer activity of berberine by activating caspase/Cyto C [72]. Judging from all the available evidential research, one can easily conclude that Melatonin effect was more predominant when it was used as an adjuvant therapy rather than using alone. The significant enhancement of Melatonin on the anticancer effect of geft- inib, berberine and doxorubicin indicates its super adjuvant property for lung cancer treatment.

Gastric cancer

Modern research also emphasized on Melatonin appli- cability in expunging Gastric cancer (GC). This type of cancer frequently produces malignant lesions with several underlying etiological array. Gastric cancer targets mucous producing cells arranged inside linings of stomach. Gas- tric cancer is the fourth most common cancer worldwide. The distinguishable anticancer activity of Melatonin is due to its multimodal mechanism of action within the cells (Fig. 3) [73]. Melatonin could enhance oxidative DNA damage due to its direct and indirect antioxidant effect. Melatonin also blocks growth factor signalling in cancer cells, leading to decreasing cancerous proliferation [74]. Melatonin also modulates internal cellular interactions to minimize metastasis. In a study performed by Li et al. had given us direction that, Melatonin could induce apoptosis in AGS cells by activating JNK and p38 mitogen-activated protein kinases [75]. Further, Melatonin suppresses the nuclear factor kappa and enhances the anti-tumour effect
of cisplatin with lower systematic toxicity. Li et al. identi- fied the apoptosis in SGC7901 gastric cancer cell lines after Melatonin treatment. Melatonin could regulate mito- gen-activated protein kinase and nuclear factor-κB signal- ling pathways to produce anticancer effect. The optimal concentration of Melatonin which requires to produce apoptosis following a 24 h treatment was found to be 2 mM [76]. One recent research by Song et al. indicated that, Melatonin could induce apoptosis and succumbed the rapid expansion of gastric cancer cells by blocking the AKT/MDM2 pathway. In this study, researcher used pro- tein chip technology to analyse resultant protein changes after Melatonin treatment with SGC-7901 gastric can- cer cells. The results show downregulation of CDC25A, phospho-CDC25A (atSer75), p21 (p21Cip1/p21Waf1) and phospho-p21 (at Thr145) proteins. There is plenty of lit- erature which emphasized Melatonin-induced apoptosis in G2/M phase in Murine Foregastric Carcinoma (MFC) cells. Additionally, Melatonin treated SGC7901 cancer cells showed more unlikely morphologic phenotype in comparison with untreated cells. These changes occur due to upregulation of gene expression of endocan and downregulation of lactate dehydrogenase and alkaline phosphatase [77]. As a whole, Melatonin has shown a sig- nificant inhibitory effect on the proliferation of gastric can- cer cells. The lurking mechanism on vandalizing gastric cancer cells is mainly includes inhibiting angiogenesis, promoting apoptosis and immunoregulation effect.
Oral cancer

As far as oral cancer is concerned, there are plenty of reports to understand the importance of Melatonin role to eradi- cate squamous cell carcinomas [76]. In one study Melatonin shows Melatonin could inhibit the effects of post metastatic genes such as ROCK-I and pro-angiogenic genes [78]. Fur- thermore, Melatonin could inhibit the actions of HIF-1α AND VEGF in SCC9 cell lines [78]. As per Yeh et al., Melatonin could reduce the signal amplitude of 12-O-tetra- decanoylphorbol-13-acetate-induced migration of oral cell lines like HSC-3 and OECM-1. Further Melatonin could supress the phosphorylation of the ERK1/2 signalling path- way. Hence, Melatonin has the capability to inhibit the motility of HSC-3 and OECM-1 and attenuating MMP-9 expression and activation mediated by decreased histone acetylation [78]. One very recent study explained that, Mela- tonin could weakened the apoptosis and proliferation of oral cancer cells by scuppering the action of ROS-dependent Akt signalling and extracellular regulated protein kinase (ERKs), which result into the inhibition of vasculogenic mimicry of oral cancer cells [79]. Additionally, Melatonin could down- regulate D1, PCNA and Bcl-2 and upregulate Bax proteins

as well. Altogether, Melatonin could exert an antimotility and antisurvival and anti-angiogenesis effect on oral cancer by inhibiting ROS-reliant Akt or ERK signalling. Collec- tively, Melatonin has shown a good anti-proliferative effect against some oral cancer cells.

Liver cancer

Melatonin also has a good anticancer effect on liver cancer or hepatocellular carcinoma. Liver cancer is the most fre- quent cancer in the developing countries claims the second most common cause of cancer death globally. The best solution available for this treatment is surgery but it is prerequisite to have a good alternative chemotherapeutic treatment to tackle this disease. The effect of melatonin was reported in several articles to tackle hepatocellular carcinoma. It was confirmed that hepatocellular carcinoma growth depends on the release of vascular endothelial growth factor (VEGF) release [80]. Melatonin induces apoptosis in Hepatocellular carcinoma (HCC) is due to these cancerous cells suffers hypoxia. This phenomenon increases the stability of hypoxia inducible factor 1 alpha (Hif1a) and signal transducer and activate transcription (STAT3) [81]. Melatonin could produce anti-angiogenic activity in Human hepatocellular carcinoma cells (HepG2) by influencing the transcriptional activation of endothelial growth factor (VEGF) [82]. As per Ordoñez et al. research, it was witnessed that 1 mm Melatonin dose was capable enough to reduce IL-1β-induced HepG2 cells and hinder cell inversion and downregulate MMP-9 gene expres- sion and upregulate the MMP-9-specific inhibitor tissue of metalloproteinases (TIMP)-1 [83]. Melatonin could specifically supress IL-1β-induced nuclear factor-kappaB (NF-κB) translocation and transcriptional. Furthermore, Melatonin could also reduce Hif1α protein expression and STAT3 activity, by which anti-angiogenic effects of Mela- tonin was recorded in HepG2 human liver cancer cells [84]. Melatonin having tendency to supress survivin and XIAP (members of inhibitors of apoptosis protein (IAPs)) by activating COX-2/P13 K/AKT pathway, by which Mela- tonin could overcome apoptosis resistance in human hepa- tocellular carcinoma [85]. Some other scattered research suggesting that the upregulation of Bcl-2-interacting medi- ator expression by FoxO3a, MT1 receptor modulation, depilation of cAMP, activation of MAPK/ERK pathway were the other important reasons to the shown anticancer effect on HepG2 human liver cancer cells by Melatonin [86]. In mice model, Melatonin reversed the alteration caused by N-nitosodiethylamine induced liver tumour in liver marker enzymes [87]. Furthermore, it also alters the circadian clock distribution and antioxidant effect in mice. Another study on rat model concluded that, by ingest- ing apoptosis and activating endoplasmic reticulum(ER)
stress, Melatonin could alter the pathway signalling of diethylnitrosamine induced Hepatocellular carcinoma, to produce the well anti cancerous effect. Overall Melatonin has a good credential to inhibit all forms of Hepatocellular carcinoma cells.

Renal cancer

Some research articles also highlighting the anti-metastatic effect of Melatonin in renal cell carcinoma (RCC) [88]. Renal cancer is very aggressive male predominant cancer which affects at list 3% male population across the globe every year. Melatonin could activate NF-kB DNA-binding and inhibit Akt-MAPKs pathway and MMP-9 transactiva- tion, to produce the anti-metastatic effect. As per Neri et al. 10 mg Melatonin daily oral dose in renal cell carcinoma patients (RCC) could activate T-cells and release cytokines [88]. In another study, it was found that Melatonin also induced apoptosis in the post and pre transcriptional level by upregulating Bim in renal cancer Caki cells [89]. Moreo- ver, as an adjuvant, Melatonin (1 mM) has a very good syn- ergistic effect with thapsigargin (50 nM) to target human renal cancer cells as compare to thapsigargin therapy alone. In another research, it was confirmed that Melatonin and kahweol co-administration could enhance DNA fragmenta- tion of Caki renal cells by stimulating DEVDase protein and upregulating p53 pathway to induce apoptosis [89]. Signifi- cantly, inhibiting metastasis and inducing apoptosis on renal cancer cell carcinoma were the two main effects which make Melatonin as an anticancer agent along with co-adminis- tration of other therapeutics. But as per recent FDA report published in the eHealthMe bulletin, kidney cancer was reported after daily Melatonin consumption among female (60 +) patients who are having prehistory of higher blood cholesterol level. Still more fundamental research need to be a warrant to know long-term side effects of Melatonin in cancer patients.

Melatonin role in other cancer research

As per various research output it is very tangible that, Mela- tonin has an important role to succumb mainstream cancer proliferation [90]. However, the anticancer effect of Mela- tonin was also been reported in some other cancer cells as well. A study revealed that Melatonin could decrease the cell viability of B16F10 melanoma cells by upregulating P13 K/
Akt/TOR pathway [91]. In melanoma, the most dangerous form of skin cancer where unpaired DNA damage occurs in skin cells due to overexposure of ultraviolet radiation to pro- duce rapid multiplication of cancerous cells [92], Melatonin can play a vital role to eradicate this form of cancer [93]. Melatonin enhances the anticancer effects of fisetin by inhib- iting NF-kB/p300 and COX-2/iNOS signalling pathways and

energizing cytochrome c-dependent apoptosis pathway [94]. In another study Melatonin also showed anticancer effects on pituitary prolactin secretory tumour. In male rate model, Melatonin-induced apoptosis by activating mitochon- drial dysfunction and increasing the ATP production [95]. In human leiomyosarcoma (LMS) also Melatonin has an anticancer effect. By suppressing the effect of linoleic acid uptake and aerobic glycolysis, Melatonin showed significant inhibitory effects on tissue isolated LMS Xenografts [96]. In human alveolar rhabdomyosarcoma, Melatonin could induce cell death in dose and time-dependent manner [97]. Another study showed mice incubated with Ehrlich ascites tumour cells had good oncostatic and cytotoxic effects after Mela- tonin treatment at 150 and 300 µg/30 g be for 12 consecutive days [98]. Furthermore, Melatonin has a good anticancer effect on pulmonary adenocarcinoma A549 cells, glioblas- toma A172 cells, chondrosarcoma sw-1353 cells, human acute myeloid leukaemia HL-60 cell [99]. By downregulat- ing function and the expression of adenosine triphosphate- binding cassette transporter ABCG2/BCRP, Melatonin and some chemotherapeutics could exhibit anticancer effect synergistically. Melatonin also showed an anticancer effect against N-MC human Ewing sarcoma cancer cells when administered with vincristine and ifosfamide [100]. Col- lectively, Melatonin has multiple mechanisms which is responsible for the various anticancer effect of Melatonin. Critically, Melatonin plays a vital role to eradicate various cancer cells when applied conjointly with some chemothera- peutic medications. To understand more effectively Table 1 discussed about recent advancements of scientific research to eradicate cancer with the help of Melatonin.
Melatonin and clinical trials

It has been already established through several clinical research that Melatonin has an unequivocal role in can- cer treatment [101]. Melatonin as an adjuvant seems to be very effective for early-stage cancer than the stage four or metastatic cancer [102]. Its agonistic property also helps to dethrone side effects associated with radiotherapy and chemotherapy. However, all these research data show less cytotoxicity of Melatonin over a vivid range of doses. The oral administration of 0.5 mg or more of Melatonin instan- taneously makes itself available in blood plasma but it does not mimic the endogenous profile [103]. But repeated and a higher administrative dose of Melatonin can desensitize receptors. Surprisingly, no significant rebound symptoms and tolerance were reported after clearance of Melatonin from the blood. Some other clinical research evidence sug- gested that Melatonin could increase therapeutic efficacy and toxicity of some anticancer drugs [104]. According to a clinical research, in colorectal cancer patient, combination

 

 
therapy of lower dose subcutaneous Interleukin-2 (3 million IU/day for 6 days for 4 weeks) and Melatonin (40 mg/day orally) noticeably increased the 1 year survival rate as com- pare with non-Melatonin based Interleukin oral dose (9/25 vs. 3/25, p < 0.05) [105]. Subordinately, in another phase II clinical research [106], Metadata of fourteen breast cancer patients show that oral 20 mg/day of Melatonin indication seven days before Tamoxifen therapy did not increase the toxicity of Tamoxifen and controlled anxiety level within 4/14 patients. Most importantly, serum levels of IGF-1 were decreased drastically due to this combination therapy. In a metastatic solid tumour, Melatonin deplete the toxicity and enhances the efficacy of chemotherapeutic drugs. In non- small cell lung cancer (NSCL) patients, 20 mg/day oral administration of Melatonin reported higher overall tumour regression rate and 5 years of survival while treating the patients with the chemotherapeutic regiment (cisplatin and etoposide). In a similar fashion, [107] Barni et al. did an extensive clinical research on the effect of colon cancer progression under 5-fluorouracil and folates, after induction of low dose IL-2 plus and Melatonin [108]. The study was designed with 50 metastatic colorectal patients. For dose administrations, patients were randomly selected and two type of treatment was planned. At first, supportive care was implemented and in second, low dose subcutaneous IL-2 (3 million IU/day for 6 days for weeks) with Melatonin (40 mg/
day orally) were administered. One group, which was treated with supportive care (25 patients) shows no tumour regres- sion occurrence. Where else, a partial tumour regression occurs (3out of 25 patients) treated with immunotherapy. The percentage survival rate was low for those patients who trod with supportive care. Where else, those patients who were treated with immunotherapy has a higher percentage of survival at 1 year (3/25 vs. 9/25, p < 0.05). This study established the low dose of subcutaneous IL-2 and mela- tonin can be used as a second line therapy for 5-FU and folates induced colon cancer therapy. In another study of 30 metastatic colorectal patients, low dose of Irinotecan and Melatonin (20 mg/day) effect was compared with lone irinotecan treated patients. The efficacy of Melatonin and Irinotecan treat patients shows 87% of stability in cancer progression. However, those patients who were treated with Irinotecan alone has only 43.7% of disease stability. In some randomized controlled design, it was found that the growth rate of Non-Small Cell Lung Cancer (NSCLC) was slow- down during induction of low dose of Cisplatin and 10 mg/
day dose of Melatonin together [109]. However, 40 mg/day Melatonin treatment in patients with advanced lung cancer did not produce any myelotoxic effects while administrating with two chemotherapeutic drugs (Carboplatin and Etopo- side) [110]. Toxicity also markedly lowers in immunother- apy treated patients as compared to those who treated with chemotherapy. In another randomized controlled study, 70

patients with advanced NSCLC was treated with first-line chemotherapeutic drugs (Cisplatin and Etoposide) or same chemotherapeutic drug combination with 20 mg/day Mela- tonin [111]. Those patients who were treated with the com- bination of chemotherapeutic drugs and Melatonin shows 44.1% of 1 year survival and 32.3% of tumour responses. Where else, only chemotherapeutic treatment shows 17.1% of 1 year survival and 19.4% of tumour responses. From the meta-analysis of 5 years randomized controlled study, it was observed that tumour regression rate was significantly higher in patients concomitantly treated with chemothera- peutics and Melatonin combination. During prospective phase II trial in Breast cancer patients, it was observed that Melatonin has a very significant role in controlling sleep quality, improving social and cognitive functional scale, improving sleep fragmentation and influencing the global quality of life. From the randomized clinical trials, it was observed that 6 mg of oral Melatonin consumption for patients improvise depression symptoms as compared to placebo-treated patients. As per Pittsburgh Sleep Quality Index (PSQI) assessment [112], oral Melatonin consump- tion before bedtime significantly increases sleep quality and it improves sleep onset for 2 week postoperative patients. The combination therapy of Melatonin with somatostatin, retinoids, vitamin D3 and a low dose of Cyclophosphamide has a paramount effect in terms of survival of breast cancer in a human [113]. But short-term Melatonin treatment did not have any prophecy to influence stage 0-III breast cancer and estradiol and IGF-1/IGBBP-3 levels [114]. The perva- sive importance of Melatonin in recent clinical research for various cancer treatments were gaudily explained in Table 2.
Future imminent and conclusions

Melatonin was first discovered by dermatologist Aaron Lerner on 1958. Since then, Melatonin (MLT) has revealed itself to be a pervasive and functionally manifold mol- ecule. The Nobel laureate and eminent Turkish scientist and biochemist Aziz Sancar had a tremendous contribu- tion to understanding the basic mechanisms of Melatonin in various human physiological conditions. Surprisingly, in different human organs and cells, Melatonin receptors are present unequivocally. In earlier days, MTL was considered as chronobiotic and chronobiologic regulator. But in recent years many research outcomes of Melatonin suggesting that it has good antioxidant and anticancer effects. All through 24-h Melatonin profile in human physiology has certain paramount effects such as controlling circadian rhythm, glu- cose hypostasis, blood pressure controlling, phosphocalcic metabolism and haemostasis etc. In this substantial review, an attempt was made to highlight the effect of Melatonin on various cancer cell prognoses. From the recent research

 
articles, it has been excavated that Melatonin has stipulated anticancer effects on colorectal, gastric, oral, prostate, ovar- ian, breast, lungs, pancreatic, liver, renal and cervical cancer cells. The underlying mechanisms of Melatonin involved in neutralizing cancerous cells were modulation of Melatonin receptors MT1 and MT2, pro-survival signalling, regula- tion of apoptosis, inhibition of angiogenesis, induction of epigenetic alteration, invasion and metastasises. Melatonin also playing a key role as an adjuvant to eradicate cancer cells while incorporating with chemotherapeutic agents. While administrating with chemotherapeutics, Melatonin reinforces therapeutic effects and reduce chemotherapy- induced side effects, enhance antioxidant effects, enhance immune stimulatory mechanisms within cells. As per Meta and clinical data analysis, it was witnessed, Melatonin might help to improve sleeping and quality of life in cancer patients. However, the omnipresent expression of ROR fam- ily’s nuclear receptors during Melatonin treatment was still poorly understood. More cell lines and animal models study need to be a warrant to understand different mechanisms and pathways involved in the anticancer effect of Melatonin. In future, there must be some good epidemiological research to overcome challenges in sample collection and assessment methods of Melatonin. Astonishingly, a most appropriate time of sample (urine, plasma, serum) collection needs to be optimized as Melatonin concentration fluctuates with the circadian rhythm. There is not much molecular research has been performed till date to study the effect of Melatonin during cellular autophagy (Unconditional programmed cell death) and mitophagy (selective degradation of mitochon- dria). A significant number of randomized controlled study or crossover design need to be performed in human volun- teers to understand the long-term safety effect, mechanisms and anticancer effect of Melatonin.

Acknowledgements The authors would like to acknowledge the exten- sive moral support given by the students and the faculty members of Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University) while compiling this manuscript.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflicts of interest.

 

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