1 INTRODUCTION

The hormone melatonin was isolated from bovine pineal glands and the chemical structure was found to be N-acetyl-5-methoxytryptamine. This pineal hormone was further characterized and described to have melanin pigment aggregation properties in frogs by Lerner and his coworkers.^1-5 Melatonin binds to specific receptors present on the surface of the chromatophores.^{6, 7} Non-cutaneous pigment cells can be found inside the body tissues such as at peritoneal sites or in the eyes, the reason for it is little understood. And some of these non-dermal types of chromatophores are also responsive to melatonin.^8-10 Melatonin is generally considered to be responsible for the centripetal lodging of pigments in melanophores of fishes and amphibians resulting in their body blanching.¹¹ Recently Kulczykowska et al.¹² have reported that the stress hormone cortisol stimulates melatonin secretion from flounder skin explants in a dose-dependent fashion. This indicates that melatonin and its metabolites can mediate the cutaneous antioxidative defense in fish, as for mammals like extrapineal melatonin synthesis¹³; even beneficial to protect mitochondria in human retinal pigment epithelium under oxidative stress.^{14, 15} Moreover, mammalian expression of retinal melatonin is regulated by the enzyme arylalkylamine N-acetyltransferase.¹⁶ Besides integrating the circadian oscillators, melatonin and its metabolites are considered potential neutralizers against pathological changes that include skin ageing and cancerogenesis.^{17, 18} Melatonin exerts an antimigrating and antiproliferative effect on the cell culture melanoma model by interrupting the cytoskeleton organization. However, this pharmacological phenomenon cannot be translated in vivo in the murine model.¹⁹ This review summarizes the effects of melatonin on mammalian pigmented cells and melanoma cells as well. An attempt has been made to analyse the varied effects observed in the melanocytes of skin and hair with seemingly appropriate inference for the tumorous melanoma cells.

2 EFFECTS ON MAMMALS

Lerner et al.²⁰ proposed a possible existence of melatonin hormone in peripheral nerves of mammals with its likely role in nerve impulse transmissions and pathogenesis of vitiligo and malignant melanomas. He also hypothesized that excess secretion at peripheral nerve endings in the skin of melatonin lightens the colour of pigment cells and reduces fresh melanin formation causing the hair to turn grey. The effective role of melatonin in affecting pigmentary events in man remains ambiguous.^{21, 22}

Snell²³ while studying prolonged administration of large doses of melatonin found no grossly observable changes in epidermal melanocytes of skin in guinea pigs. However, the effects of melatonin have been claimed on mammals concerning pathological pigment cells.^24-26 But, the unclear results also got accumulated.^{27, 28} Pigment cell response to melatonin remains absent in mammals.^{29, 30} Implantation of melatonin through beeswax resulted in the development of white winter hair in normal brown weasels and thus affects pelage colouration.³¹

Pelage colour change is paced up by exposure of winter season animals to long photoperiods, and this increase in pace is delayed by the application of melatonin. The trend of melatonin secretions from the pineal gland is important in mediating photoperiodic effects including pelage colour change in male Djungarian hamsters—Phodopus sungorus.^{32, 33} The influence of melatonin on human skin pigmentation was found to be uncertain as Nordlund and Lerner³⁴ reported that melatonin pales down hyperpigmented skin of one patient having untreated adrenogenital syndrome but did not affect three patients' skin having idiopathic hyperpigmentation and one patient cured of Addison's disease. For cultured hair follicles from Siberian hamsters, melatonin stops, through the cyclic GMP-dependent pathways of the basal, MSH or cAMP-stimulated melanogenesis with post-tyrosinase mechanisms.^35-37 Melanocytes in the uvea of the eyes remained unresponsive to melatonin.³⁸ Melatonin controls the amount of light reaching the photoreceptor by controlling the movement of melanosome pigments within the retinal pigment epithelium. Interaction of pigmented cells of guinea pigs with melatonin aggregates those cells in the retinal pigment epithelium and choroid of the eye³⁹; similar were the results in hamsters.⁴⁰

Melatonin reduced coat darkening slightly in young yellow mice in vivo when their hair re-growth after shaft plucking was examined.⁴¹ Melatonin and short photoperiods have induced testis regression and fur whitening in the summer and autumn seasons but not in winter for the mountain hairs.⁴² Total time of circadian melatonin elevation is the important parameter determining its effect on gonads and pelage,⁴³ similar reports were observed in female hamsters⁴⁴ and mice.⁴⁵ Melatonin weakly changes the electrical activity of retinal pigment epithelium.^46-48 Pineal effects on yearly changes in body weight and coat colour are affected via pituitary in Djungarian hamsters.⁴⁹ Melanocytes of the inner ear remain refractory towards melatonin.⁵⁰ Slominski et al.⁵¹ have proposed that degeneration of melanocytes in vitiligo results from a series of reactions initiated by dysregulation of melanogenesis, due to the activation of melatonin receptors.

Mammalian melanocytes and melanoma cells possess specific melatonin receptors.^52-56 Another finding by Potenza et al.⁵⁷ states that melatonin stops the melanocyte-stimulating hormone-induced cAMP accumulation in a concentration-related manner leading to pigment aggregation. A study by McElhinney et al.⁵⁸ reveals that melatonin influences mammals' coat colour and the skin colour of amphibians when applied exogenously; however, they concluded that melatonin does not affect human skin pigmentation. Melatonin stops melanogenesis in anagen skin, and hair follicle melanocytes in the skin could be the direct target cells.⁴⁵ Human skin melanocytes respond to changes in the duration of UV exposure. These responses are affected by two indoleamines, serotonin and melatonin. Increasing levels of melatonin decrease the pigment donation and dendricity of melanocytes in the photoresponse of the G₂ phase of the cell cycle. However, melatonin increases the cell number specifically when melanocytes are exposed to a pulse of UV during dark incubation, in other words, the ratio of melatonin +ve melanocytes rises with decreasing UV exposure.^59-62

Treatment of melanocytes with melatonin, before the incubation of melanotropin, mediated inhibition of α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis even at the melatonin level of 10 nM. This suggests inhibition of the starting of tyrosinase synthesis.⁶³ Melatonin causes autoimmune demyelinating processes of experimental autoimmune encephalomyelitis and multiple sclerosis.⁶⁴ Melatonin receptors appear to be negatively coupled to the enzyme adenylate cyclase in human and rat retinal pigment cells and are sensitive to pertussis toxin.⁶⁵ The application of melatonin ointment significantly lowers the count of DOPA-positive melanocytes in black mice.⁶⁶ Normal and malignant epidermal melanocytes of humans do show their gene expression for melatonin receptors (MT1 and MT2) and melatonin is also capable to mediate DNA repair/protection functions through nuclear receptors. Melatonin receptors exist ubiquitously almost everywhere in the human body.^67-69 The hormone does not affect the pigmentation of cultured hair follicles in humans.⁷⁰ Another report says that in humans melatonin modulates the hair follicle pigmentation under physiological conditions but is not a major factor in this action.⁷¹ Oral treatment of melatonin significantly decreases pigmentation in melasma patients.⁷² According to Bertolesi and MacFarlane,⁷³ melatonin secretion phased with environmental illuminance regulates seasonal and circadian variation in skin colour, this process is affected by melanopsin-expressing eye cells in mammals. Figure 1 shows the antitumour effects of melatonin.⁷⁴

3 EFFECTS ON MELANOMA CELLS

Melatonin in cultured melanoma cell lines has yielded responses that are either insignificant or variable.^75-77 Matsumoto et al.^{78, 79} developed a goldfish tumour cell line in which melanized tumour cells have been grouped as type-I and type-II melanocytomas and melanophoromas. Melanophoroma cells show pigment translocation in response to epinephrine, melatonin and/or melanocyte-stimulating hormone, whereas melanocytoma cells do not. Melatonin's influence on melanoma growth in vivo has been accepted as this hormone inhibits melanoma growth.^{80, 81} However, these in vivo effects of melatonin upon tumour growth are secondary to effects on other hormonal systems.⁸² A study shows melatonin can be administered safely by the oral route to patients with metastatic melanoma.⁸³

In hamster melanomas, melatonin signals its effects coupled through phosphoinositide hydrolysis.⁸⁴ In Cloudman mouse and Bomirski hamster amelanotic melanoma cells, melatonin administration causes inhibition of cell proliferation at low (physiological) concentrations but did not affect the synthesis of melanocytes, while at high (pharmacological) doses it causes inhibition of melanogenesis induction but does not affect cell growth. Thus, the antagonistic behaviour of melatonin is indicated against initiating factors of melanogenesis (L-tyrosine or MSH), as the already melanized or noninduced cells did not react to melatonin.⁵³ MSH-stimulated melanogenesis was found to be blocked by melatonin in B16 melanoma cells through the inhibition of tyrosinase activity probably by curtailing the induction of tyrosinase de novo synthesis. Pharmacological doses of melatonin reduced the number of a-MSH receptors to about 75%. Regarding morphological colour changes, melatonin slightly reduces tyrosinase activity but significantly inhibits α-MSH-stimulated melanogenesis in mouse melanoma cells.⁶³

Melatonin at very low concentrations inhibits the growth of uveal melanoma cells, but not the normal melanocytes, this is presumably triggered by melatonin and MT₂ activation receptors. And was found efficient in the treatment of metastatic dermal melanoma and effective against melanoma cell line proliferation.^{56, 85, 86} In skin, melatonin has been experimentally involved in melanoma control and fur pigmentation; further, the melatonin–mitochondria axis controls skin functions designed to protect local and perhaps overall body homeostasis.^{87, 88} It is an effective anticancerous compound on the melanoma cell line SK-MEL-1.⁸⁹ During the low basal activity of indoleamine 2,3-dioxygenase 1 (tryptophan catabolism), melatonin obstructs the proliferation of human melanoma cells. Melatonin can check melanoma growth as it impairs melanoma invasion in skin-reconstructed models inhibiting the multiplication of melanoma.^90-92 This pineal hormone and its derivatives can serve the purpose of excellent protectors of melanocytes against UVB-induced pathology.⁹³ It potentiates the vemurafenib-induced antitumor effect in melanoma. The combination stops in vitro and in vivo melanoma cell growth.⁹⁴ Melatonin potentially affects melanoma proliferation, melanin content and mitochondrial functions.⁹⁵ The therapeutic benefits of melatonin in the treatment of melanoma have been recently discussed by Fatemi et al.⁹⁶

Sevilla et al.⁹⁷ have also found that melatonin and its metabolites inhibit melanogenesis as well as melanocyte multiplication by stimulating the melatonin receptors MT1 and MT2. As depicted in Figure 2, we can say that this ubiquitous⁹⁸ hormone melatonin shows multipurpose roles in maintaining the physiology of the living systems.

4 MAJOR OPEN QUESTIONS

5 CONCLUSIONS AND PERSPECTIVES

AUTHORS CONTRIBUTIONS

MM performed the detailed analysis of the available literatures and the figures. NA meticulously carried out the first thorough revision of this draft. HNS provided some full-text literatures that further developed the concept of this paper. MO was our main mentor who motivated to start this article and used to check regularly. All the authors have read and approved the final manuscript.

CONFLICT OF INTEREST

The authors report no conflicts of interest.