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Anticancer properties of melatonin and its role as an adjuvant in cancer treatment


 Department of Anaesthesiology, Ibra Hospital, North Sharqiya Governorate, Ministry of Health-Oman, Ibra, Sultanate of Oman

Date of Submission20-Oct-2020
Date of Decision26-Dec-2020
Date of Acceptance15-Mar-2021
Date of Web Publication29-Jun-2022

Correspondence Address:
Abhijit Nair,
Department of Anaesthesiology, Ibra Hospital, North Sharqiya Governorate, Ministry of Health-Oman, Ibra
Sultanate of Oman
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_1197_20

  Abstract 


Melatonin is an important hormone secreted from the pineal gland that mediates several biological functions in humans through circadian rhythm. The multimodal properties of melatonin when administered systemically have generated a lot of interest among researchers. The anticancer properties of melatonin per se and its importance in cancer patients when used as an adjunct to ongoing chemotherapy and radiotherapy have led to tremendous research in animals and humans with encouraging results. The present write-up discusses the current evidence of using melatonin as an adjunct in hormone-dependent and hormone-independent cancers.


Keywords: Keywords: Angiogenesis, apoptosis, cancer, melatonin, neoplasm recurrence



How to cite this URL:
Nair A. Anticancer properties of melatonin and its role as an adjuvant in cancer treatment. Indian J Cancer [Epub ahead of print] [cited 2022 Aug 7]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=348447





  Introduction Top


The pineal gland, also known as epiphysis cerebri, is a pine cone–shaped unpaired gland about 0.8 cm long weighing about 0.1 g in adults. It is located between the thalamic bodies behind the habenular commissure near the corpora quadrigemina, which is behind the third ventricle, outside the blood–brain barrier, and it is surrounded by cerebrospinal fluid flowing through the pineal recess.[1] Melatonin (N-acetyl-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland.[2] It is produced exclusively in the night with the production and secretion totally dependent on the length of the night. Melatonin is also synthesized in lymphocytes, bone marrow, eyes, and gastrointestinal tract other than in the pineal gland.[3] Being a hormone of great physiological importance, it was initially thought that the anticancer effects of melatonin could possibly be mediated through involvement in several reactions of the endocrine system. Therefore, melatonin was explored for cancers of breast, prostate, and uterine origin. Later it was explored by researchers extensively, which opened newer avenues for the use of melatonin in cancers such as lung, brain, colorectal, gastrointestinal, liver, renal, and oral malignancies.[4],[5]

Reactive oxygen species (ROS) are produced in the body either due to exposure to carcinogens or due to various metabolic factors that cause damage to deoxyribonucleic acid (DNA), which triggers the malignancy of a particular cell line. ROS is further classified as free oxygen radicals and non-radical ROS. Increased levels of ROS in cancer are due to increased metabolic activity, mitochondrial dysfunction, peroxisome activity, increased cellular receptor signaling, oncogene activity, increased activity of oxidases, cyclooxygenases (COX), lipo-oxygenases, and thymidine phosphorylase.

The first line of defense against the free radicals is the antioxidant enzymes that neutralize ROS. They are superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GRx). There are metabolic antioxidants that are produced endogenously in the body. They are melatonin, lipoic acid, glutathione, l-arginine, coenzyme Q10, uric acid, bilirubin, metal-chelating proteins, and transferrin. There are certain exogenous antioxidants that, although not produced in the body, can be taken as part of food or are available as supplements in the market. They are vitamins C and E, trace elements (zinc, selenium, manganese), omega fatty acids, carotenoids, and flavonoids.[6] Natural killer (NK) lymphocytes that in health occupy around 15% of lymphocytes in circulation offer the first line of defense against transforming malignant cells by destroying the malignant cells by exocytosis or apoptosis.[7]

Melatonin in cancer

Instability of genome is one of the crucial events in the development and progression of cancer. According to researchers, once a genome is unstable, the measures to alter genome instability are prevention of DNA damage, stimulation of DNA repair system, deficient DNA repair targeting, targeting impaired clustering of the centrosome, and telomerase activity inhibition.[8] Cancer development is associated with sustained proliferation of malignant cells due to the altered expression of proteins and signaling pathways. To interfere with this sustained proliferation, several pathways could be targeted, which could potentially inhibit cancer proliferation. These pathways are signaling pathways of hypoxia-inducible factor-1 (HIF-1), nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase (PI3K/Akt), insulin-like growth factor 1 receptor (IGF-1R), cyclin-dependent kinases (CDKs), and estrogen receptor signaling. Experimental studies have demonstrated that melatonin inhibited sustained proliferative signaling by targeting the above-mentioned factors in various cancers.[9]

Melatonin is a hormone secreted by the pineal gland, which has been found to have several favorable properties that can be utilized in several cancers as an adjuvant to ongoing chemotherapy and radiotherapy. Melatonin downregulates certain growth factors that are responsible for cancerous growth of certain cell lines such as prolactin–IGF-1, growth hormone–dependent growth factors (GHFs), epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), transforming growth factor (TGF), and platelet-derived growth factors (PDGF).[10] Melatonin causes inhibition of adenyl cyclase and cyclic AMP (cAMP) causing a reduction in the uptake of linoleic acid, which is considered the mechanism of its antiproliferative effects. On the contrary, melatonin facilitates apoptosis mitochondrial-dependent activation route of cysteine-aspartase, which irreversibly destroys malignant cells. At physiological concentrations (1–100 nM), melatonin use 1 to 2 weeks prior to definitive chemotherapy has shown to have oncostatic properties by various mechanisms that are different for hormone-dependent and hormone-independent cancers [Table 1] and [Table 2]. Menéndez-Menéndez and Martínez-Campa reviewed the available literature to investigate the oncostatic properties of melatonin in hormone-dependent cancers when used as an adjuvant with radiotherapy and chemotherapy.[11] The authors concluded that melatonin cotherapy allows clinicians to use lower doses of chemotherapeutic agents thus causing lesser toxicity and thus to protect from the unwanted side effects of radiotherapy and most of the chemotherapy regimens. Melatonin possesses properties because of which it can scavenge the ROS or can stimulate the repair of unstable or damaged DNA in cancer.[12]
Table 1: Mechanism of anticancer effects of melatonin in hormone-dependent cancers

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Table 2: Mechanism of anticancer effects of melatonin in hormone-independent cancers

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The evasion of antigrowth pathways is another mode of cancer proliferation of cancers of various cell lines. The use of melatonin in certain hematological malignancies and prostate cancer revealed that it induced phosphorylation of p53 at Ser-15 causing proliferation inhibition and prevention of DNA damage accumulation.[27],[28]

The anticancer effects of melatonin are owing to its antioxidant effect, estrogenic receptor expression, depletion of telomerase activity, apoptosis and differentiation, antiangiogenesis, epigenetic alteration, cell cycle arrest, and activation of the immune response.[29] In experimental studies, melatonin has been shown to suppress tumor metastases by regulating cell adhesion, facilitating extracellular matrix remodeling, facilitating cytoskeleton reorganization, and manipulating epithelial–mesenchymal transition and angiogenesis at the molecular and cellular levels.[30] The antimetastatic properties of melatonin can be used as an adjunct during surgeries when the cancer cell dissemination is expected due to handling and resection. Cancer cells are known to be resistant to apoptosis due to overexpression of antiapoptotic proteins that inhibit the process of apoptosis. Restoring apoptotic mechanisms has been considered beneficial in preventing cancer progression. When used in certain hematological cancers, such as prostate, liver, pancreas, and ovarian cancers, melatonin has demonstrated downregulation of antiapoptotic proteins and upregulation of proapoptotic proteins.[31] Replicative immortality is a characteristic of cancer cells due to which they divide continuously and thus can undergo unlimited cycles of cell division. To address this inhibition of telomerase, mammalian target of rapamycin (mTOR), CDK4/6, CDK 1/2/5/9, Akt, and PI3K is necessary. Use of melatonin has led to the inhibition of these pathways in head and neck cancer, breast cancer, and hepatoma.[32] Metabolism dysregulation in the form of increased glucose uptake and lactate production (the Warburg effect) is a characteristic feature observed in cancer cells. The mediators of this phenomenon are hypoxia-inducible factor 1 (HIF1) and MYC oncogene. With use of melatonin, it was observed that there was reduction in lactate by inhibition of lactate dehydrogenase in certain cancer cell lines and downregulation of MYC oncogene.[33] Ongoing inflammation can have deleterious effects on cancer patients. Melatonin possesses anti-inflammatory effects that are mediated via inhibition of COX-2 expression, upregulation of proapoptotic proteins, and inhibition of inducible nitric oxide synthase (iNOS).[34]

Unlike chemotherapy or radiotherapy wherein the treatment could affect the normal cell lines also, melatonin has no untoward effects on normal, healthy cells. Along with melatonin, its metabolites such as cyclic-3-hydroxymelatonin (cyclic-3OHM), 6-hydroxymelatonin (6-OHmel), N(1)-acetyl-5-methoxykynuramine (AMK) has also displayed antioxidant effects by scavenging ROS and radical reactants.[35]

The importance of melatonin in circadian rhythm is extensively studied and well understood. Many clinicians have explored the role of interference in melatonin secretion due to exposure to artificial light during sleep time and altered sleep habits leading to malignancy of breast tissue. Several studies have shown that the incidence of breast cancer in women is directly proportional to light exposure at nighttime. The nocturnal exposure to light inhibits melatonin release and thus increases susceptibility to breast malignancy, particularly seen in women working in night shifts. Women with vision disturbances, including blindness, have lesser chances of developing breast cancer compared with women with normal vision.[36] A Similar hypothesis was explored for cancers of uterine and prostate origin. In the past few decades, researchers have explored the various properties of melatonin in hormone-dependent and hormone-independent malignancies as an adjuvant used with chemotherapy and to reduce the side effects of chemotherapy and radiation.[37]

Mechanism of action of melatonin

Melatonin offers its various functions through MT1 and MT2 receptors, which are G-protein-coupled receptors and are associated with seven transmembrane domains both causing inhibition of adenylyl cyclase. MT1 receptors also activate protein kinase C-β, whereas MT2 receptors also inhibit the guanylate cyclase pathway 39 and stimulates protein kinase C.[38] MT3 receptors that are found in the liver, kidney, heart, lung, intestine, muscle, and brown fat tissue are also described. It has a role in the regulation of intraocular pressure. The antitumor effect of melatonin has been proposed to be due to MT1/MT2-dependent inhibition of linoleic acid uptake. Melatonin also binds to calmodulin (CaM), tubulin, and nuclear receptors of the retinoic acid receptor (ROR) family, RORα1, RORα2, and RZRα. Melatonin influences intracellular CaM distribution, which in turn inhibits cell cycle progression.[39] The association of the use of melatonin and its effects on breast cancer has been the most widely studied and researched in animals and humans alike. The breast cell lines involved and the pathways involved in offering protection at various levels are depicted in [Table 1]. One of the most important anticancer effects of melatonin in breast cancer is by acting as a CaM antagonist.[40] Pariente et al. explored the role of melatonin receptors in the cytotoxicity and apoptosis induced by cisplatin and 5-fluorouracil in human colorectal cancer HT-29 cells and cervical cancer HeLa cells.[41] On investigation, the authors concluded that when used in vitro melatonin enhanced chemotherapy-induced cytotoxicity in the above-mentioned cell lines and that this potentiation was facilitated by MT3 receptor stimulation.

Another important therapeutic effect of melatonin in cancer patients is interference in the secretion of VEGF.[42] Metastasis is facilitated by the breakdown of extracellular matrix (ECM) by matrix metalloproteinases (MMPs), which in turn liberates VEGF and fibroblast growth factors, which eventually promotes metastasis by breaking down of ECM and causing angiogenesis and lymphangiogenesis. Melatonin inhibits MMP activity and along with other effects such as anti-inflammation and immune enhancement interferes with metastasis in several cancers.[43] Endothelin-1 (ET-1) is an endogenous vasoconstrictor that is responsible for tumor angiogenesis by upregulating VEGF and MMP in certain cancer cell lines. Melatonin has been shown to reduce the secretion and expression of ET-1, thus interfering with angiogenesis.[26] The other mechanisms involved in antiangiogenesis are by downregulation of p38 signaling pathway, inhibition of hypoxia-induced cell migration by inhibiting ERK/Rac1 pathway, and inhibition of endothelin-1.[44]

As per available evidence in animal studies and human cell lines, melatonin exerts beneficial effects in cancers of various cell lines because of its multimodal mechanisms in all phases, that is, initial, progressive, and metastatic phases.[45] It can serve as a useful adjuvant to chemotherapeutic regimens with or without radiation therapy. The role of melatonin has been explored not only in hormone-dependent cancers but also in hormone-independent cancers and has been supported by evidence.[46]

As an oral preparation with a dose of 10 to 20 mg/day, melatonin is easily tolerated and does not have any noteworthy adverse effect profile.[47] Commonly encountered adverse events are nausea, dizziness, headache, and weight gain in some patients. Timing of administration is important because it should not be given in daytime.[48],[49] The timing of initiating melatonin prior to chemotherapy for its antiapoptotic effects has not been defined yet. Once there is enough evidence regarding the dose and duration of the therapy, it could be an important adjuvant in indicated patients.


  Conclusion Top


Present data regarding the use of melatonin as an adjuvant for cancer treatment suggest that it improves remission rate, overall survival rate, and also reduces the severity of side effects due to prescribed chemotherapy such as neurotoxicity, bone marrow suppression, and asthenia. Melatonin has been found useful in hormone-dependent and hormone-independent malignancies. Right now, there are no published data on anticancer efficacy of melatonin as an adjuvant in different types of cancers from the Indian subcontinent. Well-designed studies are the need of the hour to introduce melatonin in patients undergoing cancer treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2]



 

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