Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

molecules Review Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities Wamidh H. Talib 1,* , Ahmad Riyad Alsayed 1, Alaa Abuawad 2, Safa Daoud 3 and Asma Ismail Mahmod 1 1 Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman 11931, Jordan; [email protected] (A.R.A.); [email protected] (A.I.M.) 2 Department of Pharmaceutical Sciences and Pharmaceutics, Faculty of Pharmacy, Applied Science Private University, Amman 11931, Jordan; [email protected] 3 Department Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman 11931, Jordan; [email protected] * Correspondence: [email protected] Abstract: Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreas- ing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer Citation: Talib, W.H.; Alsayed, A.R.; Abuawad, A.; Daoud, S.; Mahmod, using melatonin. A.I. Melatonin in Cancer Treatment: Current Knowledge and Future Keywords: pineal gland; anticancer; cancer therapy; hormonal therapy; phytomelatonin Opportunities. Molecules 2021, 26, 2506. https://doi.org/10.3390/ molecules26092506 1. Introduction Academic Editor: Dun-Xian Tan Melatonin (N-acetyl-5-methoxytryptamine) is an indole amine produced in the human body by multiple sources. It is mainly produced by the pineal gland in response to darkness. Received: 26 February 2021 Other organs that synthesize melatonin include skin, bone marrow, lymphocytes, retina, Accepted: 19 April 2021 and gastrointestinal tract [1] Published: 25 April 2021 Suprachiasmatic nucleus (SCN) of the hypothalamus is the biological clock that regu- lates melatonin synthesis and secretion over 24 h [2]. At night, melatonin levels increase, Publisher’s Note: MDPI stays neutral then start to decrease in the early morning and throughout the day. Elevated levels of mela- with regard to jurisdictional claims in tonin at night stimulate target organs to enter into suitable homeostatic metabolic rhythms published maps and institutional affil- which help to protect the body from the development of different diseases [3]. Therefore, iations. exposing the body to light at night may result in disruption of melatonin production and the circadian rhythm. Cancer is a growing health problem that needs an urgent response to control it. A prediction from the World Health Organization’s International Agency for Research on Copyright: © 2021 by the authors. Cancer Global Cancer Observatory (GLOBOCAN) expected 27.5 million cancer cases every Licensee MDPI, Basel, Switzerland. year by 2040. These values represent a 61.7% increase compared with current statistics [4]. This article is an open access article Nowadays, cancer patients depend mainly on conventional anticancer therapies includ- distributed under the terms and ing surgery, radiotherapy, and chemotherapy. Additionally, many plant-derived natural conditions of the Creative Commons products were reported to have a direct role in cancer prevention and therapy [5]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ During the last decades, evidences were accumulating to support the diverse roles of 4.0/). melatonin in human physiology and pathology. Currently, melatonin is considered as a Molecules 2021, 26, 2506. https://doi.org/10.3390/molecules26092506 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 45 Molecules 2021, 26, 2506 2 of 46 cell protector and not only a hormone. Studies reported essential effects of melatonin in cell protector and not only a hormone. Studies reported essential effects of melatonin in many pathways, including oxidative stress, immune modulation, and hematopoiesis [6,7]. many pathways, including oxidative stress, immune modulation, and hematopoiesis [6,7]. Additionally, a a large large number number of of studies studies confirmed confirmed the the anticancer anticancer and and oncostatic oncostatic effects effects of melatoninof melatonin mediated mediated by by different different mechanisms mechanisms of of action action [8,9]. [8,9]. Moreover, Moreover, melatonin melatonin was used in combination anticancer therapies to augment conventional therapies and reduce sideside effects effects [8–10]. [8–10]. This review summarizes recent findings findings on the anticancer properties of melatonin and its mechanisms of action. Melatonin Melatonin biosynthesis, biosynthesis, bioavailability, bioavailability, natural natural sources, cancercancer preventivepreventive properties,properties, pharmaceutical pharmaceutical formulation, formulation, and and its useits use in clinical in clinical trials trials were werediscussed discussed in this in review. this review. 2. Melatonin Melatonin Biosynthesis Biosynthesis and and Metabolism Metabolism in Human Body Melatonin was was isolated isolated in in 19 1958,58, by by the the dermatologist dermatologist Aaron Aaron Lerner, Lerner, from from bovine bovine pin- ealpineal gland. gland. Although Although it is itmainly is mainly secreted secreted from from the pineal the pineal gland, gland, there there are many are many other other sec- ondarysecondary sources sources including; including; retina, retina, gut, gut, skin skin,, platelets platelets and and bone bone marrow, marrow, and and probably other structures, but their systemic contribution is insignificantinsignificant [[11].11]. The starting starting material material of melatonin melatonin biosynthes biosynthesisis in humans is tryptophan, an essential amino acid. acid. Through Through the the action action of oftryptophan tryptophan hydroxylase hydroxylase (TP5H) (TP5H) and and aromatic aromatic acid acid de- carboxylasedecarboxylase (AADC), (AADC), enzymes enzymes tryptophan tryptophan is converted is converted to tothe the neurotransmitter, neurotransmitter, seroto- sero- nin.tonin. In Inthe the subsequent subsequent step, step, serotonin serotonin is is co convertednverted into into melatonin melatonin through through the the influence influence of arylalkylamine arylalkylamine N-acetyltransferase N-acetyltransferase (AANAT) (AANAT) and hydroxyindole-O-methyltransferase hydroxyindole-O-methyltransferase (HIOMT) enzymes [12] [12] (Figure 1 1).). O HO HO HO OH O TP5H AADC NH2 NH2 NH2 N N H H N H L-Tryptophan 5-hydroxytryptophan Serotonin AANAT O O O N HO N H HIOMT H N N H H Melatonin N-acetylserotonin Figure 1. Melatonin biosynthesis in human. Melatonin is is not not stored stored inside inside the the pineal pineal glan glandd and and it it is is released released as as it it is synthetized, soso the plasma hormone profile profile faithfully refl reflectsects the pineal activity [13]. [13]. Moreover, Moreover, am- am- phiphilic naturenature andand the the small small size size of melatoninof melatonin facilitates facilitates its passage its passage across across cell membranes cell mem- branesand its and access its access to various to various fluids, fluids, tissues, tissues, and cellular and cellular compartments compartments as saliva, as saliva, urine, urine, cere- cerebrospinalbrospinal fluid, fluid, preovulatory preovulatory follicle, follicle, semen, semen, amniotic amniotic fluid, fluid, and and milk milk [11,14 [11,14,15].,15]. Melatonin is metabolized metabolized mainly by cytochrome cytochrome P450 in the the liver. liver. It It has has been been demon- demon- stratedstrated that that melatonin melatonin was was metabolized metabolized to to 6-hydroxymelatonin 6-hydroxymelatonin and N-acetylserotonin by CYP1A1 and CYP 2C19, respectively, atat PhasePhase I I metabolism, metabolism, and and most most of of them them were were subse- sub- sequentlyquently converted converted to sulfateto sulfate conjugates conjugates by sulfotransferases by sulfotransferases in human in human liver and liver excreted and ex- in cretedthe urine in the [16 urine]. A small [16]. portionA small ofportion melatonin of melatonin is degraded is degraded by other by tissues other includingtissues includ- skin and brain by either CYPA2B or 2,3-indolamine dioxygenase to form 6-hydroxymelatonin Molecules 2021, 26, 2506 3 of 46 or N1-acetyl-N2-formyl-5-methoxykynurenine (AFMK). The urinary excretion probably is not the major metabolic route of AFMK judging from its water solubility [17]. Melatonin has specific receptors to regulate many physiological functions namely; MT1 and MT2, both are members of the seven transmembrane G-protein coupled receptor family [18]. Human MT1 and MT2 receptors are 350 and 362 amino acids long, respectively, with molecular weights of 39–40 kDa and 55% amino acid homology overall [19]. Both MT1

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