Next Article in Journal
The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence
Next Article in Special Issue
Melatonin May Curtail the Metabolic Syndrome: Studies on Initial and Fully Established Fructose-Induced Metabolic Syndrome in Rats
Previous Article in Journal
Parkinson’s Disease: A Complex Interplay of Mitochondrial DNA Alterations and Oxidative Stress
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Melatonin Anticancer Effects: Review

Di Bella Foundation, Via Guglielmo Marconi 51, Bologna 40122, Italy
Private Laboratory of Physiology, Via Stefano Giovanni Marianini, Modena 41123, Italy
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2013, 14(2), 2410-2430;
Submission received: 5 December 2012 / Revised: 14 January 2013 / Accepted: 15 January 2013 / Published: 24 January 2013
(This article belongs to the Special Issue Advances in the Research of Melatonin)


Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases.

1. Introduction: General Considerations on the Anticancer Effect of Melatonin

The functions of MLT involve numerous physiological processes, including circadian rhythm regulation, seasonal changes, sleep, reproduction and cardiovascular function [1]. MLT also modulates the functions of the immune and hemopoietic systems [2].
It is now accepted that MLT has marked dose-dependent antioxidative effect, providing protection against damage from carcinogenic substances, acting as a free radical scavenger [3]. This action can be reproduced experimentally, with important implications in the prevention and treatment of tumors. Numerous studies have tried to define the in vitro effects of MLT on the proliferation of tumor cell lines and on their apoptosis. There is no common agreement on why the action of MLT varies according to histological type, cell differentiation, sensitivity to oncogenic molecules and culture medium conditions [48].
The variability of MLT’s in vitro anticancer efficacy depends on the limitations and conditioning of the cell culture medium, without, obviously, the “biological context” and the complex and multifaceted interactions with which MLT exerts its anticancer properties in vivo [6]. In addition, the dynamics of division of normal cells and of tumor cells also depend on and are coordinated by a succession of MLT-correlated circadian time-markers [9].
Finally, MLT’s documented ability to negatively regulate both the transcription of the receptor gene of estrogen (ER) [1012] and the oncogenic potential of the Growth Hormone (GH) axis with Prolactin-Insulin-like Growth Factor-1 (IGF-1) and of GH-dependent growth factors, such as Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF), Platelet Derived Growth Factor (PDGF), Transforming Growth Factor (TGF), or Hepatocyte Growth Factor (HGF), are aspects that certainly have an anticancer relevance [1321].

2. The Main Direct Anticancer Mechanisms of Melatonin

2.1. Pro-Apoptotic

The direct anticancer action is exerted by inhibiting the proliferation and growth of tumor cells, thus hindering the tendency of healthy cells to become neoplastic, and inducing cellular turnover and replacement of tumor cells with healthy cells through apoptosis. The intrinsic, mitochondrial-dependent, activation route of caspases (cysteine-apartase) represents the “point of no return” towards the programmed cell death induced by MLT [2224]. Numerous studies have documented the anticancer properties of MLT in solid tumors and in leukemia, with particular efficacy in lymphoproliferative tumors [2528].
The use of MLT together with retinoic acid, on MCF-7 hormone-dependent breast cancer cells, showed a complete halt in cell growth and a reduction in the number of cells through apoptosis activation [2932].

2.2. Antiproliferative

Various studies have shown that MLT has marked oncostatic properties that can reduce the promotion or progression of the tumor. Various authors have demonstrated that the antiproliferative properties of MLT take place through inhibition/blocking of the cell cycle [3338].
This is confirmed by clinical studies in which, according to Luigi Di Bella, MLT alone cannot heal a tumor but without MLT it is difficult to heal any tumor. MLT therefore represents an absolutely necessary component in anticancer treatment, although it is not sufficient on its own [3942].
Other studies have demonstrated the direct and selective inhibitory effect of melatonin on lymphoblastoid cell growth process [2628]; El Missiry et al. studied the effect of MLT on Ehrlich ascites carcinoma cells (EAC), noting that it not only reduced their vitality and volume, increasing the survival of experimental animals, but also induced apoptosis of the EAC tumor cells [43].
A significant clinical fact emerged from a study on 250 patients with various forms of advanced and metastasized tumors, in whom the one-year survival rate and the objective tumor regression rate were much higher in the patients also treated with MLT compared to those who only received chemotherapy. Administration of MLT also significantly reduced thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis and asthenia [44].
Mediavilla, Sancez-Barcelo et al. observed an interesting oncostatic mechanism of action of MLT, through the activation and increase of p21/WAF1 and p53 suppressor genes which act by halting the reproduction cycle of tumor cells [45]. Human breast cancer cells (MCF-7) were studied in vitro, and it was found that, at physiological concentrations, MLT reduced the number and vitality of the tumor cells after 48 h. A year previously, a study was published on the effect of MLT, together with somatostatin, on murine colon cancer (colon-38), showing not only the antiproliferative effect but also an evident proapoptotic action [46].

2.3. Differentiating

At the Seventh Colloquium of the European Pineal Society at Sitges in 1966, several papers were presented on the oncostatic effect of MLT and its properties of inhibiting the metastatic spread of tumor cells. It was demonstrated that some oncogenes, including Rat sarcoma (RAS; Hras, Kras, NRas), are significantly inhibited by MLT [47]. Biochemical and molecular mechanisms of the oncostatic action of MLT also include the architecture of the cytoskeleton and the redox intracellular function. An important mediation mechanism of melatonin on the inhibitory action of the circadian-dependent growth of the tumor is the suppression of the epidermal growth factor receptor (EGFR) and of the activity of the mitogen-activated protein kinase, (MAPK) [9,48,49]. This takes place through the oxidation of linoleic acid and its conversion to 13-hydroxyoctadecadienoic (13-Hode) acid that can activate both EGFR and MAPK [50,51].

2.4. Anti-Angiogenetic

Other potential mechanisms concern the ability of melatonin to reduce tumoral angiogenesis, inhibiting the expression of the HIF-1alpha protein, inducing hypoxy in the cancer cells and acting on the Vascular Endothelial Growth Factor (VEGF) [5256].

3. The Main Indirect Anticancer Mechanisms of Melatonin

3.1. Free Radical Scavenger Action

This counters carcinogenesis by means of free anti-radical and antioxidative effects [5760]. This limits the toxicity of chemotherapy, simultaneously reinforcing the clinical response [61,62]. Chemotherapy causes an evident decrease in the serum levels of melatonin [63].

3.2. Myeloprotective/Myelostimulant Action

Myelosuppression represents a considerable problem in chemotherapy protocols. MLT protects the bone marrow and relative lymphoid tissues against the toxic effects of chemotherapy, and has a myeloprotective action with determining effects on blood composition, medullary dynamics and erythro-leuko-thrombocytopoiesis [61,62].
An essential fact discovered 30 years ago by Di Bella is the close functional interaction between MLT and platelets. This association is indispensable in understanding a number of phenomena essential not only for the physiology of blood, but of all tissues, in particular of the nervous system, both central and peripheral. The functional support of MLT is the platelet which carries it in structures of its cytoplasm, the “dense bodies”, where by means of a homeostatic mechanism it is mobilized on the basis of the plasma concentration [6468].
Conjugation with adenosine, though the hydrogen bond, according to the Luigi Di Bella formulation (Figure 1), makes MLT perfectly hydrosoluble and absorbable by the cell membranes. The platelets adhere to the wall of megakaryocytes and can release the melatonin already bound to adenosine. Melatonin can bind to ATP, ADP, AMP, polynucleic and ribonucleic acid and it is at this level that it exerts its antiblastic action [6971].

3.3. Melatonin’s Action in Regulating the Immune System

MLT is involved in the body’s cell and humoral regulation, acting as an endocrine, autocrine and/or paracrine molecule [72]. This activity is sustained by its nuclear and membrane receptorial expression, with an intrinsic characteristic of the human lymphocyte populations. The existence of specific receptors for MLT in lymphoid cells confirms this indirect effect in regulating and reinforcing the immune response [7375].
These protein binding sites have been described not only in human lymphocytes but also in granulocytes and in biological lymphoid reservoirs (thymus, spleen, bursa of Fabricius, etc.). The fundamental physiological role of MLT in the human immune system has thus been documented. Humoral regulation takes place through the production of cytokines in immunocompetent cells. MLT not only stimulates the production of natural killer cells, monocytes and leukocytes, but also increases the production of Interleukin 2-6-10-12 (IL-2-6-10-12) and Interferon-gamma (IFN-γ) by the mononucleate cells, promoting a T helper 1 (Th-1) lymphocyte response [25,7679].

4. Mechanisms of Action and Physiology of Melatonin in Tumors

4.1. The Receptorial System

Although the molecule is highly diffusible and exerts systemic effects by means of at least two intracellular processes like modulation of the mitotic and cytoskeletal functions through the bond with calmodulin [80,81] and the free radical scavenger [82], two specific receptors have been identified: MT1 and MT2 [83,84]. Initially characterized at the level of the central nervous system, the receptors for MLT have been localized in all districts and cell types, including cells of the hemopoietic system such as lymphocytes, megakaryocytes, platelets, intestinal and prostatic cells, renal tubules, and cardiac miocytes [8587]. Due to its chemical characteristics and low molecular weight (232, 278 kDa), MLT spreads easily both in extracellular liquid and in the cells themselves, in which orphan nuclear receptors have been identified [88]. From a chemical point of view, some of these nuclear receptors present structural similarities to retinoid receptors (ROR and RZR) [89,90] and the vitamin D receptor (VDR) [91,92].
These melatonin nuclear receptors are particularly widespread in the central nervous system, the main concentrations being in the pineal body, thalamus, hypothalamus, suprachiasmatic nucleus, cerebral cortex, superior colliculus of the lamina quadrigemina, habenulas, pars tuberalis, adenohypophysis and cerebellum [9397]; a more or less ubiquitary presence of the melatonin receptors can be hypothesized, further confirming the primary role of MLT in vital functions. The chemical-metabolic properties linked to these receptors can help to understand some of the anticancer mechanisms of action of MLT.
Having also foreseen these recent findings, Di Bella suggested that the main anticancer effect of MLT consisted of the ubiquitary availability of the phosphor esters of AMP, ADP, and ATP [69,98,99].
It is now accepted that MLT influences cell activity by acting mainly on the phosphor esters of adenosine and on other signal transduction systems, such as the protein C mediated inhibition of adenyl cyclase, inhibition of Ca2+ mobilization, inhibition of arachidonic acid release, action on protein kinase C, and opening of the potassium channels [100107] (Figure 2).

4.2. Other Mechanisms

Melatonin can also exerts at different physiological levels its antitumoral properties by a set of complex mechanisms of action, not necessary involving the receptor pathway. These actions consist of apoptosis activation, inhibition of proliferation and cell differentiation (Figure 2). In fact, the intracellular redox state is strongly related to the MLT antiproliferative and cytotoxic actions in cancer cells. Therefore, tumor cell fate will depend on the ability of this indolamine to induce either an antioxidant environment—related to the antiproliferative effect or a pro-oxidant environment related to the cytotoxic effect (apoptosis). First, inhibition of proliferation is correlated with a decrease on intracellular reactive oxygen species (ROS) and an increase of the sub-cellular antioxidant enzymes (CAT, SOD and GRS levels), while induction of the programmed cell death is the result of the imbalance between ROS (increased) species production and antioxidant defenses (inhibited) [35]. The enzyme activation is also a crucial point for cell differentiation in several cancer cell lines [35,108]. Moreover, the same mechanisms can be reproduced by other well-known antioxidants molecules (retinoid, alpha-tocopheryl acetate, and ascorbic acid) [59].

4.3. The Amine Precursor Uptake and Decarboxylation System (APUD)

Kvetnoi et al. [109] confirmed the active role of MLT and of the molecules produced by the Amine Precursor Uptake and Decarboxylation system (APUD), both on tumor etiopathogenesis and proliferation and in antiblastic therapy. Analysis of the physiological characteristics of many biologically active substances produced by the Diffuse Neuro-Endocrine System (DNES) [110], such as melatonin, serotonin, gastrin, insulin, glucagon, somatostatin, etc., confirms the important role of the hormones of these cells in the stages of tumor onset and proliferation, while the decrease in the number of these cells in the terminal stages of the tumor is significant [111].
Hormonal secretion in non-endocrine tumors has great theoretical and practical significance, confirmed by many authors, such as Maluf, Koerner and Bonkhoff [112,113].
The presence of endocrine cells in tumor metastases confirms the malignant nature of these cells. The authors also documented a significant correlation between the histological type of the tumor and the biological properties of the molecules it produces, i.e., MLT, serotonin, and somatostatin, all having an antiproliferative activity [114]. These substances were more frequent in the more differentiated tumors such as adenocarcinomas and squamous cell carcinomas with keratinization, while catecholamine, histamine, insulin, gastrin, and TSH, substances inducing proliferative activity, were usually more frequent in tumors that have a higher proliferative index, those that are more aggressive and less differentiating, such as solid tumors and squamous cell carcinomas without keratinization. These data suggest that the in situ production of MLT and of the relative APUD peptides in non-endocrine tumors plays a determining role in the autocrine mechanisms of tumoral homeostasis, promoting, slowing down, inhibiting or preventing progression and metastasization.
Additional confirmation comes from studies relative to the significant increase of cells that are immunopositive for MLT in non-metastatic human breast cancer [115]. Confirmation is also provided by studies on the oncostatic effect of MLT on the mammary gland in transgenic mice with N-ras proto-oncogene, which have demonstrated that MLT reduces the incidence of hyperplastic alveolar nodules and the presence of N-ras protein in focal hyperplastic lesions [47].
Maestroni and Conti found concentrations of MLT in breast cancer cells triple those of the serum rate of healthy subjects [116].
Epithelial and APUD cells originate from common stem cells and the presence of APUD cells in non-endocrine tumors depends on the level of malignant transformation. Hormonal secretion in tumors originating from non-endocrine cell aggregates is not an autonomous sign, but a genetically induced element, caused by cell genesis and differentiation. This process is directly associated with cell growth, division and differentiation potential, and the prognostic aspect deriving from the identification of the chemical composition and biological hormonal activity produced by these tumor cells should therefore not be underestimated.

4.4. Platelets and the APUD System

Platelets can be considered omnipresent, multifactorial and itinerant elements of a plastic and ubiquitary APUD system, with its content of serotonin (5-TH) and norepinephrine, acetylcholine and epinephrine, MLT, NAT and HIOMT, metabolic byproducts and deposit of adenosine (AMP, ADP, ATP). Platelets sometimes act like a melatonergic and dopaminergic, serotonergic and adrenergic neuron, depending on local conditions and the working nature of the nuclei. Platelets can absorb and store 5-TH; they can also synthesize MLT since they also contain 5-TH-decarboxylase [117,118].
There is a large quantity of pharmacological data indicating considerable functional affinity and complementary action between the platelets and neurons of the serotonergic system. This function of the platelets, which release their deposits of 5-TH and expel material from their granules when activated by appropriate stimuli has been considered very similar to the release of neurotransmitters by central neurons. The platelet release reaction and the secretion activity together act as a model for the release of central serotonergic and adrenergic neurons [119121].

4.5. Melatonin’s Action on Microtubules

MLT carried out its anticancer activity also on the intercellular gap junctions that mediate communication between adjacent cells and are closely connected to the mechanisms that condition cellular growth. A study by Kojma et al. on rat hepatocytes demonstrated the induction by MLT of the CX32 gap junction protein [122124].
The process of tubulin polymerization may also be one of the intercellular objectives of the action of MLT on tumor cells. Meléndez et al. demonstrated that physiological concentrations of MLT induce an increase of microtubules in NIE-115 neuroblastoma cells, and that this effect is due to an increase of the polymerization status of tubulin [80,125,126].

5. Melatonin and Tumor Treatment

5.1. Clinical Significance and Therapeutic Application

Several clinical trials have examined the therapeutic usefulness of melatonin in different types of cancer. The conclusion is that the use of melatonin as an adjuvant therapy seems to be very useful for early stages than for advanced and metastatic cancers [127130]. Use a strongly helpful aid for side effects caused by chemotherapy and radiotherapy administration was also reported [61,131133]. Moreover, all the investigations mentioned documented the very low toxicity of melatonin over a wide range of doses. On the basis of this preliminary studies, it seems that melatonin administration may be beneficial for oncological subjects [134137].

5.2. Future Prospects after 30 Years of Research

The absolute priority of the anticancer use of melatonin belongs to Luigi Di Bella, who believed that the antiblastic activity of MLT was not limited to the aforementioned mechanisms of action, nor to the biochemistry of MLT or of other pineal methoxyindoles [138,139]. It has also been shown that MLT can reach the nucleus of the megakaryocyte and carry out a similar action to cytochalasin B, both in inhibiting the process of endoduplication and in increasing nuclear polyploidy [140,141].
Di Bella was the first to identify the fundamental and primary role of MLT in providing the phosphor esters of AMP, ADP and ATP [69].
This concept is fundamental for the relationship and close connection with the school of thought led by Goldberger, Epstein and Anfinsen, which also allows the possibility of self-assembly and that the protein can spontaneously restore its three-dimensional structure with full biological activity (protein folding) [142].
It could be the same or another protein that influences the intermolecular reactions. Some proteins act as molecular chaperones and by hydrolyzing ATP they activate the folding of protein structures that are otherwise inert [143,144]. The mechanism of action was explained by Ellis, who identified the chaperonins as sequestrating agents containing the folded individual protein structures in the Anfinsen cage [145,146]. According to Luigi D Bella, in neoplastic biology the action of the chaperonins should prevalently take place through the hydrolysis of ATP, ADP, and AMP bonded with adenosine or MLT [69,98,99] (Figure 1).

5.3. Indications Regarding the Proposed Dosage of Melatonin in Prevention

The dosage of MLT in prevention vary according to age, sex, familiarity, current and/or previous diseases, type of activity carried out with exposure to cancerogenous molecules and/or relative to the duration of exposure and the intensity of magnetic fields. The dosage also considers nocturnal exposure at work to artificial light with relative inhibition of the pineal secretion of MLT [120,147,148]. To reinforce the immune system through the increase of interleukin 2, MLT, together with retinoids, vitamin E, vitamin C, and vitamin D3 improves the antifective and antiblastic immune responses; the dosage in prevention must therefore be increased in immunodepressed subjects [79].
In children, dosage starts with the evening administration of 2 mg, increasing gradually after adolescence. In adult males of average weight and age, 4–5 mg can be administered in the evening; slightly less in fertile age females: 2–3 mg. After the age of 50 years, especially in post-menopausal women due to MLT’s ability to inhibit potentially cancerogenous molecules, in addition to GH, such as prolactin, estrogens and androgens, the dose can be gradually increased to 10 mg [64,149151].
In the presence of fibrocystic breasts, ovarian cysts, myomas, uterine fibromas, or endometrial thickening, 15–20 mg can be administered depending on the intensity of the disease.
Similar doses can be administered also in the case of prostatic hypertrophy. In these male and female often precancerous situations, the synergism with prolactin inhibitors and retinoids solubilized in vitamins E and D3 has proved particularly useful for the documented high receptorial expression in the prostate, uterine microfibromas and breast, in addition to MLT and D2, VDR and RXR receptors. The same doses and synergism apply to nodules of the thyroid (normal or hyperfunctioning) which also have a similar receptorial expression. In the thyroid, the decrease in the volume of the nodules is accelerated by the use of somatostatin and also low doses (0.1–0.2 mg) of octreotide.

5.4. Indications Regarding the Proposed Dosage of Melatonin in the Treatment of Tumors

Although the ideal dose of melatonin has not yet been standardized, some clinical studies, in addition to our own results, have shown that daily oral doses of 20–40 mg (distributed evenly throughout the day with greater concentrations in the evening) [149151], up to a maximum of 1000 mg of Melatonin administered slowly and intravenously during the day, are perfectly well tolerated, with useful and beneficial effects for the patients [152,153]. In over 42 years of experience in the clinical use of MLT by Luigi Di Bella, Giuseppe Di Bella and others, the dose has been gradually increased, without toxicity or significant side effects, except for temporary drowsiness reported by some patients, generally at the start of the treatment, and very rarely making it necessary to reduce the dose. Patients diagnosed at an initial/early stage of the disease can be given 30 mg of melatonin orally, and the maximum dose is also advised for patients with sleeping disorders. Since numerous clinical studies have shown that patients with an advanced/terminal stage of the disease or who no longer respond to traditional treatments can benefit from the administration of high doses of MLT; these patients could consider taking a supplement of MLT of 100 mg.
The hydrogen bond with adenosine (Figure 1) improves its bioavailability, makes it hydrosoluble and forms the base molecule for the synthesis and diffusion of phosphor esters of AMP, ADP and ATP, which have a significant role in physiological and neoplastic biology, as previously described.

6. Conclusions

In the present marked cultural decline, muffled by the superficial culture of everyday events, rational technological simplification is not always able to compensate for the burden of progressive ignorance. In the health sector, costs have soared because too many unnecessary expensive, if not harmful, tests are performed, because patients are flooded with technically and aesthetically perfect but useless, if not toxic drugs, and because expensive and pointless hospital stays are prolonged.
Ignorance of the real disease and appropriate remedies to cure it is the primary cause of incorrect care, patient malaise and disproportionate balance sheets.
The cancer problem can be satisfactorily and largely resolved only by optimization, courageously eliminating the irrationality of the past, reaching out towards a future in which cancer becomes a normal occurrence of future human existence, because means will have been found and correctly applied.
If physicians remember the fundamental saying “Primum non nocere” addressed to the patient, but also and above all to their colleagues, then the health sector would undoubtedly improve. No profession is perhaps founded so much on morals as the medical profession. There are numerous famous sayings that commend this profession, some evasive and deceiving. Loving one’s fellow man would be enough, aspiring to change the expression of pain into a progressive image of acceptable prognosis, to achieve the aim. It is not too much to expect the highest level of general morality from one’s doctor.
The desire to hand on, at least in part, the ideas of Luigi Di Bella was the stimulus for publishing this review, in the hope that one day his dream would become reality. The basis for his ideas is to consider cancer as a form of life, a life that he defined as “potent, overwhelming, parasitic and anarchic”. It is necessary to combine a series of substances that can act in a centripetal way on the tumor cells and that can have an effect, from time to time, simultaneously or successively, on the myriad of biological reactions that are responsible for the life of these cells. This gave rise not to a substance but to a method [42,153].
Considering that: (a) the treatment of solid tumors is based essentially on surgery; (b) there are no statistics in the literature regarding solid tumors cured in a stable way by chemotherapy alone and that if a tumor exceeds the surgical limits, chemotherapy and/or monoclonal antibodies are unable to cure it; (c) the results of the current medical treatments for cancer are still extremely limited and are often temporary [154,155]; (d) chemotherapy treatments are penalized by toxicity, sometimes fatal [156,157]; (e) due to its mutagenic effect, chemotherapy is able to select strains of increasingly more resistant and aggressive tumor cells [158]; and (f) the increase in resistance and aggression of tumor cells can also be induced by radiotherapy [159]; we wanted to draw attention to the use of MLT in oncology, believing that, by combining the documented anticancer properties with an antitoxic, trophic, immunostimulating, differentiating, radioprotective and radiosensitizing effect, the oncotherapuetic possibilities of this pineal indole are still greatly underestimated [160166].

Conflict of Interest

The authors declare no conflict of interest.


  1. Macchi, M.M.; Bruce, J.N. Human pineal physiology and functional significance of melatonin. Front. Neuroendocrinol 2004, 25, 177–195. [Google Scholar]
  2. Skwarlo-Sonta, K. Melatonin in immunity: Comparative aspects. Neuro Endocrinol. Lett 2002, 2, 61–66. [Google Scholar]
  3. Reiter, R.J.; Korkmaz, A. Clinical aspects of melatonin. Saudi Med. J 2008, 29, 1537–1547. [Google Scholar]
  4. Suwanjang, W.; Phansuwan-Pujito, P.; Govitrapong, P.; Chetsawang, B. The protective effect of melatonin on methamphetamine-induced calpain-dependent death pathway in human neuroblastoma SH-SY5Y cultured cells. J. Pineal Res 2010, 48, 94–101. [Google Scholar]
  5. Proietti, S.; Cucina, A.; Reiter, R.J.; Bizzarri, M. Molecular mechanisms of melatonin’s inhibitory actions on breast cancers. Cell. Mol. Life Sci 2012. [Google Scholar] [CrossRef]
  6. Rodriguez-Garcia, A.; Mayo, J.C.; Hevia, D.; Quiros-Gonzalez, I.; Navarro, M.; Sainz, R.M. Phenotypicchanges caused by melatonin increased sensitivity of prostate cancer cells to cytokine-induced apoptosis. J. Pineal Res 2012. [Google Scholar] [CrossRef]
  7. Zhang, S.; Zuo, L.; Gui, S.; Zhou, Q.; Wei, W.; Wang, Y. Induction of cell differentiation and promotion of endocan gene expression in stomach cancer bymelatonin. Mol. Biol. Rep 2012, 39, 2843–2849. [Google Scholar]
  8. Gamaleĭ, I.A.; Kirpichnikova, K.M.; Filatova, N.A. Effect of melatonin on the functional properties of transformed cells. Vopr. Onkol 2011, 57, 481–485. [Google Scholar]
  9. Blask, D.E.; Sauer, L.A.; Dauchy, R.T. Melatonin as a chronobiotic/anticancer agent: Cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr. Top Med Chem 2002, 2, 113–132. [Google Scholar]
  10. Sánchez-Barceló, E.J.; Cos, S.; Mediavilla, D.; Martínez-Campa, C.; González, A.; Alonso-González, C. Melatonin-estrogen interactions in breast cancer. J. Pineal Res 2005, 38, 217–222. [Google Scholar]
  11. Bartsch, H.; Buchberger, A.; Franz, H.; Bartsch, C.; Maidonis, I.; Mecke, D.; Bayer, E. Effect of melatonin and pineal extracts on human ovarian and mammary tumor cells in a chemosensitivity assay. Life Sci 2000, 67, 2953–2960. [Google Scholar]
  12. Watanabe, M.; Kobayashi, Y.; Takahashi, N.; Kiguchi, K.; Ishizuka, B. Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line. J. Obstet. Gynaecol. Res 2008, 34, 567–573. [Google Scholar]
  13. Heldin, C.H.; Westermark, B. Platelet-derived growth factor and autocrine mechanisms of oncogenic processes. Crit. Rev. Oncog 1991, 2, 109–124. [Google Scholar]
  14. Lüscher, T.F.; Boulanger, C.M.; Dohi, Y.; Yang, Z.H. Endothelium-derived contracting factors. Hypertension 1992, 19, 117–130. [Google Scholar]
  15. Comoglio, P.M. Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells. EXS 1993, 65, 131–165. [Google Scholar]
  16. Cos, S.; Blask, D.E. Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J. Pineal Res 1994, 17, 25–32. [Google Scholar]
  17. Boonstra, J.; Rijken, P.; Humbel, B.; Cremers, F.; Verkleij, A.; van Bergen en Henegouwen, P. The epidermal growth factor. Cell Biol. Int 1995, 19, 413–430. [Google Scholar]
  18. Ornitz, D.M.; Itoh, N. Fibroblast growth factors. Genome Biol 2001, 2, 1–12. [Google Scholar]
  19. Ferrara, N.; Gerber, H.P. The role of vascular endothelial growth factor in angiogenesis. Acta Haematol 2002, 106, 148–156. [Google Scholar]
  20. Trejo, J.L.; Carro, E.; Garcia-Galloway, E.; Torres-Aleman, I. Role of insulin-like growth factor I signaling in neurodegenerative diseases. J. Mol. Med 2004, 82, 156–162. [Google Scholar]
  21. Matt, P.; Schoenhoff, F.; Habashi, J.; Holm, T.; Van Erp, C.; Loch, D.; Carlson, O.D.; Griswold, B.F.; Fu, Q.; De Backer, J.; et al. Circulating transforming growth factor-β in Marfan syndrome. Circulation 2009, 120, 526–532. [Google Scholar]
  22. Fischer, T.W.; Zmijewski, M.A.; Wortsman, J.; Slominski, A. Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/ casp-7) and PARP in UVR-exposed HaCaT keratinocytes. J. Pineal Res 2008, 44, 397–407. [Google Scholar]
  23. Ferreira Cda, S.; Maganhin, C.C.; Simões Rdos, S.; Girão, M.J.; Baracat, E.C.; Soares-Jr, J.M. Melatonin: Cell death modulator. Rev. Assoc. Med. Bras 2010, 56, 715–718. [Google Scholar]
  24. Sánchez-Hidalgo, M.; Guerrero, J.M.; Villegas, I.; Packham, G.; de la Lastra, C.A. Melatonin, a natural programmed cell death inducer in cancer. Curr. Med. Chem 2012, 19, 3805–3821. [Google Scholar]
  25. Lissoni, P.; Bolis, S.; Brivio, F.; Fumagalli, L. A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies. Anticancer Res 2000, 20, 2103–2105. [Google Scholar]
  26. Trubiani, O.; Recchioni, R.; Moroni, F.; Pizzicannella, J.; Caputi, S.; Di Primio, R. Melatonin provokes cell death in human B-lymphoma cells by mitochondrial-dependent apoptotic pathway activation. J. Pineal Res 2005, 39, 425–431. [Google Scholar]
  27. Bejarano, I.; Redondo, P.C.; Espino, J.; Rosado, J.A.; Paredes, S.D.; Barriga, C.; Reiter, R.J.; Pariente, J.A.; Rodríguez, A.B. Melatonin induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells. J. Pineal Res 2009, 46, 392–400. [Google Scholar]
  28. Sánchez-Hidalgo, M.; Lee, M.; de la Lastra, C.A.; Guerrero, J.M.; Packham, G. Melatonin inhibits cell proliferation and induces caspase activation and apoptosis in human malignant lymphoid cell lines. J. Pineal Res 2012, 53, 366–373. [Google Scholar]
  29. Eck-Enriquez, K.; Kiefer, T.L.; Spriggs, L.L.; Hill, S.M. Pathways through which a regimen of melatonin and retinoic acid induces apoptosis in MCF-7 human breast cancer cells. Breast Cancer Res. Treat 2000, 61, 229–239. [Google Scholar]
  30. Czeczuga-Semeniuk, E.; Wołczyński, S.; Anchim, T.; Dziecioł, J.; Dabrowska, M.; Pietruczuk, M. Effect of melatonin and all-trans retinoic acid on the proliferation and induction of the apoptotic pathway in the culture of human breast cancer cell line MCF-7. Pol. J. Pathol 2002, 53, 59–65. [Google Scholar]
  31. Dong, C.; Yuan, L.; Dai, J.; Lai, L.; Mao, L.; Xiang, S.; Rowan, B.; Hill, S.M. Melatonin inhibits mitogenic cross-talk between retinoic acid-related orphan receptor alpha (RORalpha) and ERalpha in MCF-7 human breast cancer cells. Steroids 2010, 75, 944–951. [Google Scholar]
  32. Margheri, M.; Pacini, N.; Tani, A.; Nosi, D.; Squecco, R.; Dama, A.; Masala, E.; Francini, F.; Zecchi-Orlandini, S.; Formigli, L. Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: Molecular basis for the anticancer effect of these molecules. Eur. J. Pharmacol 2012, 681, 34–43. [Google Scholar]
  33. Lissoni, P.; Rovelli, F.; Frassineti, A.; Fumagalli, L.; Malysheva, O.; Conti, A.; Maestroni, G. Oncostatic activity of pineal neuroendocrine treatment with the pineal indoles melatonin and 5-methoxytryptamine in untreatable metastatic cancer patients progressing on melatonin alone. Neuro Endocrinol. Lett 2000, 21, 319–323. [Google Scholar]
  34. Tam, C.W.; Chan, K.W.; Liu, V.W.; Pang, B.; Yao, K.M.; Shiu, S.Y. Melatonin as a negative mitogenic hormonal regulator of human prostate epithelial cell growth: Potential mechanisms and clinical significance. J. Pineal Res 2008, 45, 403–412. [Google Scholar]
  35. Sánchez-Sánchez, A.M.; Martín, V.; García-Santos, G.; Rodríguez-Blanco, J.; Casado-Zapico, S.; Suarez-Garnacho, S.; Antolín, I.; Rodriguez, C. Intracellular redox state as determinant for melatonin antiproliferative vs. cytotoxic effects in cancer cells. Free Radic. Res 2011, 45, 1333–1341. [Google Scholar]
  36. Cabrera, J.; Negrín, G.; Estévez, F.; Loro, J.; Reiter, R.J.; Quintana, J. Melatonin decreases cell proliferation and induces melanogenesis in human melanoma SK-MEL-1 cells. J. Pineal Res 2010, 49, 45–54. [Google Scholar]
  37. Pizarro, J.G.; Yeste-Velasco, M.; Esparza, J.L.; Verdaguer, E.; Pallàs, M.; Camins, A.; Folch, J. The antiproliferative activity of melatonin in B65 rat dopaminergic neuroblastoma cells is related to the downregulation of cell cycle-related genes. J. Pineal Res 2008, 45, 8–16. [Google Scholar]
  38. Martín, V.; Herrera, F.; Carrera-Gonzalez, P.; García-Santos, G.; Antolín, I.; Rodriguez-Blanco, J.; Rodriguez, C. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006, 66, 1081–1088. [Google Scholar]
  39. Di Bella, L. Melatonin: An Essential Factor for the Treatment and Recovery from Leukemia and Cancer. Proceedings of International Symposium on Melatonin, Bremen, Germany, September 1980; pp. 161–162.
  40. Lissoni, P.; Barni, S.; Cattaneo, G.; Tancini, G.; Esposti, G.; Esposti, D.; Fraschini, F. Clinical result with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991, 48, 48–50. [Google Scholar]
  41. Bubenik, G.A.; Blask, D.E.; Brown, G.M.; Maestroni, G.J.; Pang, S.F.; Reiter, R.J.; Viswanathan, M.; Zisapel, N. Prospects of the clinical utilization of melatonin. Biol. Signals Recept 1998, 7, 195–219. [Google Scholar]
  42. Di Bella, G. The Di Bella Method (DBM). Neuro. Endocrinol. Lett 2010, 31, 1–42. [Google Scholar]
  43. El-Missiry, M.A.; Abd El-Aziz, A.F. Influence of melatonin on proliferation and antioxidant system in Ehrlich ascites carcinoma cells. Cancer Lett 2000, 151, 119–125. [Google Scholar]
  44. Lissoni, P.; Barni, S.; Mandala, M.; Ardizzoia, A.; Paolorossi, F.; Vaghi, M.; Longarini, R.; Malugani, F.; Tancini, G. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. Eur. J. Cancer 1999, 35, 1688–1692. [Google Scholar]
  45. Mediavilla, M.D.; Cos, S.; Sanchez-Barcelo, E.J. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 1999, 65, 415–420. [Google Scholar]
  46. Mełen-Mucha, G.; Winczyk, K.; Pawlikowski, M. Somatostatin analogue octreotide and melatonin inhibit bromodeoxyuridine incorporation into cell nuclei and enhance apoptosis in the transplantable murine colon 38 cancer. Anticancer Res 1998, 18, 3615–3619. [Google Scholar]
  47. Mediavilla, M.D.; Güezmez, A.; Ramos, S.; Kothari, L.; Garijo, F.; Sánchez Barceló, E.J. Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene. J. Pineal Res 1997, 22, 86–94. [Google Scholar]
  48. Haus, E.; Dumitriu, L.; Nicolau, G.Y.; Bologa, S.; Sackett-Lundeen, L. Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer. Chronobiol. Int 2001, 18, 709–727. [Google Scholar]
  49. Luchetti, F.; Betti, M.; Canonico, B.; Arcangeletti, M.; Ferri, P.; Galli, F.; Papa, S. ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells. Free Radic Biol. Med 2009, 46, 339–351. [Google Scholar]
  50. Silverman, A.L.; Bronstein, J.C.; Krymgold, S.; Kahlon, D.; Bull, A.W. Decreased levels of 13-hydroxyoctadecadienoic acid (13-HODE) dehydrogenase in neoplastic tissue of human colon biopsies. Cancer Epidemiol. Biomark. Prev 1996, 5, 53–56. [Google Scholar]
  51. Hill, S.M.; Blask, D.E.; Xiang, S.; Yuan, L.; Mao, L.; Dauchy, R.T.; Dauchy, E.M.; Frasch, T.; Duplesis, T. Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer. J. Mammary Gland Biol. Neoplasia 2011, 16, 235–245. [Google Scholar]
  52. Lissoni, P.; Rovelli, F.; Malugani, F.; Bucovec, R.; Conti, A.; Maestroni, G.J. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol. Lett 2001, 22, 45–47. [Google Scholar]
  53. SoybIr, G.; Topuzlu, C.; OdabaS, O.; Dolay, K.; Bilir, A.; Oksoy, K.F. The effects of melatonin on angiogenesis and wound healing. Surg. Today 2003, 33, 896–901. [Google Scholar]
  54. Alvarez-García, V.; González, A.; Alonso-González, C.; Martínez-Campa, C.; Cos, S. Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J. Pineal Res 2012. [Google Scholar] [CrossRef]
  55. Park, S.Y.; Jang, W.J.; Yi, E.Y.; Jang, J.Y.; Jung, Y.; Jeong, J.W.; Kim, Y.J. Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J. Pineal Res 2010, 48, 178–184. [Google Scholar]
  56. Kim, K.J.; Choi, J.S.; Kang, I.; Kim, K.W.; Jeong, C.H.; Jeong, J.W. Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model. J. Pineal Res. 2012. [Google Scholar] [CrossRef]
  57. Karbownik, M. Potential anticarcinogenic action of melatonin and other antioxidants mediated by antioxidative mechanisms. Neuro Endocrinol. Lett 2002, 23, 39–44. [Google Scholar]
  58. Vijayalaxmi; Reiter, R.J.; Tan, D.X.; Herman, T.S.; Thomas, C.R., Jr. Melatonin as a radioprotective agent: A review. Int. J. Radiat. Oncol. Biol. Phys. 2004, 59, 639–653. [Google Scholar]
  59. Kadoma, Y.; Fujisawa, S. Radical-scavenging activity of melatonin, either alone or in combination with vitamin E, ascorbate or 2-mercaptoethanol as co-antioxidants, using the induction period method. In Vivo 2011, 25, 49–53. [Google Scholar]
  60. Galano, A. On the direct scavenging activity of melatonin towards hydroxyl and a series of peroxyl radicals. Phys. Chem. Chem. Phys 2011, 13, 7178–7188. [Google Scholar]
  61. Anwar, M.M.; Mahfouz, H.A.; Sayed, A.S. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp. Biochem. Physiol. A 1998, 119, 493–501. [Google Scholar]
  62. Rapozzi, V.; Zorzet, S.; Comelli, M.; Mavelli, I.; Perissin, L.; Giraldi, T. Melatonin decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing TLX5 lymphoma. Life Sci 1998, 63, 1701–1713. [Google Scholar]
  63. Lissoni, P.; Bastone, A.; Sala, R.; Mauri, R.; Rovelli, F.; Viviani, S.; Bajetta, E.; Esposti, D.; Esposti, G.; Di Bella, L.; et al. The clinical significance of melatonin serum determination in oncological patients and its correlations with GH and PRL blood levels. Eur. J. Cancer Clin. Oncol 1987, 23, 949–957. [Google Scholar]
  64. Di Bella, L.; Rossi, M.T.; Pellegrino, N.; Grimaldi, A.; Santoro, V. Ruolo dei sistema abenulo-epifisario nella regolazione del tasso-piastrinemico. Boll. Soc. It. Biol. Sper 1969, 45, 171. [Google Scholar]
  65. Rossi, M.T.; Scalera, G.; Di Bella, L. Azione mielotropa della melatonina (MLT). Boll. Soc. It. Biol. Sper 1976, 52, 26. [Google Scholar]
  66. Rossi, M.T.; Di Bella, L. Melatonin in Thrombocytogenesis. In The Pineal Gland and Cancer. Brain Research Promotion; Gupta, D., Attanasio, A., Reiter, R.J., Eds.; Brain Research Promootion: Tubingen, Germany, 1988; pp. 183–194. [Google Scholar]
  67. Gualano, L.; Di Bella, L.; Rossi, M.T.; Scalera, G. Effetti della melatonina sui megacariociti viventi di midollo di ratto. Boll. Soc. It. Biol. Sper 1977, 53, 44. [Google Scholar]
  68. Cardinali, D.P.; Del Zar, M.M.; Vacas, M.I. The effects of melatonin in human platelets. Acta Physiol. Pharmacol. Ther. Latinoam 1993, 43, 1–13. [Google Scholar]
  69. Di Bella, L.; Bucciarelli, M.; Pagnoni, U.M.; Scalera, G.; Rossi, M.T. Formazione di complessi tra melatonina (mlt) e basi puriniche e pirimidiniche. Boll. Soc. It. Biol. Sper 1976, 52, 157. [Google Scholar]
  70. Rossi, M.T.; Di Bella, L.; Scalera, G.; Gualano, L. Platelet Turnover as Influenced by Melatonin. Presented at International Symposium on Melatonin, Bremen, Germany, 28–30 September 1980.
  71. Jeffrey, G.A.; Saenger, W. Hydrogen Bonding in Biological Structures; Springer-Verlag: Berlin, Germany, 1991; p. 569. [Google Scholar]
  72. Carrillo-Vico, A.; Calvo, J.R.; Abreu, P.; Lardone, P.J.; García-Mauriño, S.; Reiter, R.J.; Guerrero, J.M. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: Possible role as intracrine, autocrine, and/or paracrine substance. FASEB J 2004, 18, 537–539. [Google Scholar]
  73. Hill, S.M.; Spriggs, L.L.; Simon, M.A.; Muraoka, H.; Blask, D.E. The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett 1992, 64, 249–256. [Google Scholar]
  74. Gonzalez-Haba, M.G.; Garcia-Mauriño, S.; Calvo, J.R.; Goberna, R.; Guerrero, J.M. High-affinity binding of melatonin by human circulating T lymphocytes (CD4+). FASEB J 1995, 9, 1331–1335. [Google Scholar]
  75. García-Pergañeda, A.; Pozo, D.; Guerrero, J.M.; Calvo, J.R. Signal transduction for melatonin in human lymphocytes: Involvement of a pertussis toxin-sensitive G protein. J. Immunol 1997, 159, 3774–3781. [Google Scholar]
  76. Konakchieva, R.; Kyurkchiev, S.; Kehayov, I.; Taushanova, P.; Kanchev, L. Selective effect of methoxyindoles on the lymphocyte proliferation and melatonin binding to activated human lymphoid cells. J. Neuroimmunol 1995, 63, 125–132. [Google Scholar]
  77. Garcia-Mauriño, S.; Gonzalez-Haba, M.G.; Calvo, J.R.; Rafii-El-Idrissi, M.; Sanchez-Margalet, V.; Goberna, R.; Guerrero, J.M. Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: A possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J. Immunol 1997, 159, 574–581. [Google Scholar]
  78. Lissoni, P.; Rovelli, F.; Brivio, F.; Brivio, O.; Fumagalli, L. Circadian secretions of IL-2, IL-12, IL-6 and IL-10 in relation to the light/dark rhythm of the pineal hormone melatonin in healthy humans. Nat. Immun 1998, 16, 1–5. [Google Scholar]
  79. García-Mauriño, S.; Pozo, D.; Carrillo-Vico, A.; Calvo, J.R.; Guerrero, J.M. Melatonin activates Th1 lymphocytes by increasing IL-12 production. Life Sci 1999, 65, 2143–2150. [Google Scholar]
  80. Benítez-King, G.; Antón-Tay, F. Calmodulin mediates melatonin cytoskeletal effects. Experientia 1993, 49, 635–641. [Google Scholar]
  81. Soto-Vega, E.; Meza, I.; Ramírez-Rodríguez, G.; Benitez-King, G. Melatonin stimulates calmodulin phosphorylation by protein kinase C. J. Pineal Res 2004, 37, 98–106. [Google Scholar]
  82. Tan, D.X.; Reiter, R.J.; Manchester, L.C.; Yan, M.T.; El-Sawi, M.; Sainz, R.M.; Mayo, J.C.; Kohen, R.; Allegra, M.; Hardeland, R. Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger. Curr. Top. Med. Chem 2002, 2, 181–197. [Google Scholar]
  83. Naji, L.; Carrillo-Vico, A.; Guerrero, J.M.; Calvo, J.R. Expression of membrane and nuclear melatonin receptors in mouse peripheral organs. Life Sci 2004, 74, 2227–2236. [Google Scholar]
  84. Girgert, R.; Hanf, V.; Emons, G.; Gründker, C. Membrane-bound melatonin receptor MT1 down-regulates estrogen responsive genes in breast cancer cells. J. Pineal Res 2009, 47, 23–31. [Google Scholar]
  85. Lopez-Gonzalez, M.A.; Calvo, J.R.; Osuna, C.; Rubio, A.; Guerrero, J.M. Synergistic action of melatonin and vasoactive intestinal peptide in stimulating cyclic AMP production in human lymphocytes. J. Pineal Res 1992, 12, 174–180. [Google Scholar]
  86. Vacas, M.I.; Del Zar, M.M.; Martinuzzo, M.; Cardinali, D.P. Binding sites for [3H]-melatonin in human platelets. J. Pineal Res 1992, 13, 60–65. [Google Scholar]
  87. Calvo, J.R.; Rafii-el-Idrissi, M.; Pozo, D.; Guerrero, J.M. Immunomodulatory role of melatonin: Specific binding sites in human and rodent lymphoid cells. J. Pineal Res 1995, 18, 119–126. [Google Scholar]
  88. Mangelsdorf, D.J.; Evans, R.M. The RXR heterodimers and orphan receptors. Cell 1995, 83, 841–850. [Google Scholar]
  89. Wiesenberg, I.; Missbach, M.; Kahlen, J.P.; Schräder, M.; Carlberg, C. Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification od CGP 52608 as a synthetic ligand. Nucleic Acids Res 1995, 23, 327–233. [Google Scholar]
  90. Renaud, J.P.; Rochel, N.; Ruff, M.; Vivat, V.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature 1995, 378, 681–689. [Google Scholar]
  91. Yu, X.P.; Mocharla, H.; Hustmyer, F.G.; Manolagas, S.C. Vitamin D receptor expression in human lymphocytes. Signal requirements and characterization by western blots and DNA sequencing. J. Biol. Chem 1991, 266, 7588–7595. [Google Scholar]
  92. Adorini, L.; Daniel, K.C.; Penna, G. Vitamin D receptor agonists, cancer and the immune system: An intricate relationship. Curr. Top. Med. Chem 2006, 6, 1297–1301. [Google Scholar]
  93. Morgan, P.J.; Barrett, P.; Howell, H.E.; Helliwell, R. Melatonin receptors: Localization, molecular pharmacology and physiological significance. Neurochem. Int 1994, 24, 101–146. [Google Scholar]
  94. Mazzucchelli, C.; Pannacci, M.; Nonno, R.; Lucini, V.; Fraschini, F.; Stankov, B.M. The melatonin receptor in the human brain: cloning experiments and distribution studies. Brain Res. Mol. Brain Res 1996, 39, 117–126. [Google Scholar]
  95. Weaver, D.R.; Reppert, S.M. The Mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei. Neuroreport 1996, 8, 109–112. [Google Scholar]
  96. Al-Ghoul, W.M.; Herman, M.D.; Dubocovich, M.L. Melatonin receptor subtype expression in human cerebellum. Neuroreport 1998, 9, 4063–4068. [Google Scholar]
  97. Dubocovich, M.L.; Markowska, M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2005, 27, 101–110. [Google Scholar]
  98. Di Bella, L. Orientamenti fisiologici nella terapia delle emopatie. Bull. Sc. Med 1974, 145, 1–3. [Google Scholar]
  99. Di Bella, L.; Rossi, M.T.; Scalera, G. Perspectives in pineal function. Prog. Brain Res 1979, 52, 475–478. [Google Scholar]
  100. Kornblihtt, L.I.; Finocchiaro, L.; Molinas, F.C. Inhibitory effect of melatonin on platelet activation induced by collagen and arachidonic acid. J. Pineal Res 1993, 14, 184–191. [Google Scholar]
  101. Garcia-Perganeda, A.; Guerriero, J.M.; Rafii-El-Idrissi, M.; Paz Romero, M.; Pozo, D.; Calvo, J.R. Characterization of membrane melatonin receptor in mouse peritoneal macrophages: Inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein. J. Neuroimmunol 1999, 95, 85–94. [Google Scholar]
  102. Di Bella, L.; Bruschi, C.; Gualano, L. Melatonin effects on megakaryocyte membrane patch-clamp outward K+ current. Med. Sci. Monit. 2002, 8, BR527–531. [Google Scholar]
  103. Steffens, F.; Zhou, X.B.; Sausbier, U.; Sailer, C.; Motejlek, K.; Ruth, P.; Olcese, J.; Korth, M.; Wieland, T. Melatonin receptor signaling in pregnant and nonpregnant rat uterine myocytes as probed by large conductance Ca2+-activated K+ channel activity. Mol. Endocrinol 2003, 17, 2103–2115. [Google Scholar]
  104. Hou, S.W.; Zheng, P.; Sun, F.Y. Melatonin inhibits outward delayed rectifier potassium currents in hippocampal CA1 pyramidal neuron via intracellular indole-related domains. J. Pineal Res 2004, 36, 242–249. [Google Scholar]
  105. Sampson, S.R.; Lupowitz, Z.; Braiman, L.; Zisapel, N. Role of protein kinase C-alpha inmelatonin signal transduction. Mol. Cell. Endocrinol 2006, 252, 82–87. [Google Scholar]
  106. Martín, V.; Herrera, F.; García-Santos, G.; Antolín, I.; Rodriguez-Blanco, J.; Medina, M.; Rodriguez, C. Involvement of protein kinase C in melatonin’s oncostatic effect in C6 glioma cells. J. Pineal Res 2007, 43, 239–244. [Google Scholar]
  107. Quiros, I.; Mayo, J.C.; Garcia-Suarez, O.; Hevia, D.; Martin, V.; Rodríguez, C.; Sainz, R.M. Melatonin prevents glucocorticoid inhibition of cell proliferation and toxicity in hippocampal cells by reducing glucocorticoid receptor nuclear translocation. J. Steroid Biochem. Mol. Biol 2008, 110, 116–124. [Google Scholar]
  108. Sainz, R.M.; Mayo, J.C.; Tan, D.X.; León, J.; Manchester, L.; Reiter, R.J. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate 2005, 63, 29–43. [Google Scholar]
  109. Kvetnoi, I.M.; Raikhlin, N.T. Clinical pathology of the APUD system (apudopathy). Klin. Med. (Mosk) 1978, 56, 15–22. [Google Scholar]
  110. Polak, J.M.; Bloom, S.R. The diffuse neuroendocrine system. Studies of this newly discovered controlling system in health. J. Histochem. Cytochem 1979, 27, 1398–1400. [Google Scholar]
  111. Raikhlin, N.T.; Kvetnoi, I.M. APUD system and neuroendocrine tumors (“apudomas”). Arkh. Patol 1997, 39, 74–80. [Google Scholar]
  112. Maluf, H.M.; Koerner, F.C. Carcinomas of the breast with endocrine differentiation: A review. Virchows Arch 1994, 425, 449–457. [Google Scholar]
  113. Bonkhoff, H.; Stein, U.; Remberger, K. Endocrine-paracrine cell types in the prostate and prostatic adenocarcinoma are postmiotic cells. Hum. Pathol 1995, 26, 167–170. [Google Scholar]
  114. Raikhlin, N.T.; Kvetnoi, I.M. The APUD system (diffuse endocrine system) in normal and patological states. Physiol. Gen. Biol. Rev 1994, 8, 1–44. [Google Scholar]
  115. Sanchez-Barcelo, E.J.; Mediavilla, M.D.; Tucker, H.A. Influence of melatonin on mammary gland growth: in vivo and in vitro studies. Proc. Soc. Exp. Biol. Med 1990, 194, 103–107. [Google Scholar]
  116. Maestroni, G.J.; Conti, A. Melatonin in human breast cancer tissue: Association with nuclear grade and estrogen receptor status. Lab. Invest 1996, 75, 557–561. [Google Scholar]
  117. Del Zar, M.M.; Martinuzzo, M.; Cardinali, D.P.; Carreras, L.O.; Vacas, M.I. Diurnal variation in melatonin effect on adenosine triphosphate and serotonin release by human platelets. Acta Endocrinol. (Copenh) 1990, 123, 453–458. [Google Scholar]
  118. Champier, J.; Claustrat, B.; Besançon, R.; Eymin, C.; Killer, C.; Jouvet, A.; Chamba, G.; Fèvre-Montange, M. Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets. Life Sci 1997, 60, 2191–2197. [Google Scholar]
  119. Zucker, M.B.; Borrelli, J. Quantity, assay and release of serotonin in human platelets. J. Appl. Physiol 1955, 7, 425–431. [Google Scholar]
  120. Marmaras, V.J.; Mimikos, N. Enzymic formation of serotonin in mammalian blood platelets and red cells. Experientia 1971, 27, 196–197. [Google Scholar]
  121. Martín, F.J.; Atienza, G.; Aldegunde, M.; Míguez, J.M. Melatonin effect on serotonin uptake and release in rat platelets: Diurnal variation in responsiveness. Life Sci 1993, 53, 1079–1087. [Google Scholar]
  122. Ubeda, A.; Trillo, M.A.; House, D.E.; Blackman, C.F. A 50 Hz magnetic field blocks melatonin-induced enhancement of junctional transfer in normal C3H/10T1/2 cells. Carcinogenesis 1995, 16, 2945–2949. [Google Scholar]
  123. Kojima, T.; Mochizuki, C.; Mitaka, T.; Mochizuki, Y. Effects of melatonin on proliferation, oxidative stress and Cx32 gap junction protein expression in primary cultures of adult rat hepatocytes. Cell Struct. Funct 1997, 22, 347–356. [Google Scholar]
  124. Cos, S.; Fernandez, R. Melatonin effects on intercellular junctional communication in MCF-7 human breast cancer cells. J. Pineal Res 2000, 29, 166–171. [Google Scholar]
  125. Meléndez, J.; Maldonado, V.; Ortega, A. Effect of melatonin on beta-tubulin and MAP2 expression in NIE-115 cells. Neurochem. Res 1996, 21, 653–658. [Google Scholar]
  126. Benitez-King, G.; Túnez, I.; Bellon, A.; Ortíz, G.G.; Antón-Tay, F. Melatonin prevents cytoskeletalalterations and oxidative stress induced by okadaic acid in N1E-115 cells. Exp. Neurol 2003, 182, 151–159. [Google Scholar]
  127. Mills, E.; Wu, P.; Seely, D.; Guyatt, G. Melatonin in the treatment of cancer: A systematic review of randomized controlled trials and meta-analysis. J. Pineal Res 2005, 39, 360–366. [Google Scholar]
  128. Lissoni, P. Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathol. Biol. (Paris) 2007, 55, 201–204. [Google Scholar]
  129. Sánchez-Barceló, E.J.; Mediavilla, M.D.; Tan, D.X.; Reiter, R.J. Clinical uses of melatonin: Evaluation of human trials. Curr. Med. Chem 2010, 17, 2070–2095. [Google Scholar]
  130. Seely, D.; Wu, P.; Fritz, H.; Kennedy, D.A.; Tsui, T.; Seely, A.J.; Mills, E. Melatonin as adjuvant cancer care with and without chemotherapy: A systematic review and meta-analysis of randomized trials. Integr. Cancer Ther 2012, 11, 293–303. [Google Scholar]
  131. Wang, Y.M.; Jin, B.Z.; Ai, F.; Duan, C.H.; Lu, Y.Z.; Dong, T.F.; Fu, Q.L. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: A meta-analysis of randomized controlled trials. Cancer Chemother. Pharmacol 2012, 69, 1213–1220. [Google Scholar]
  132. Lissoni, P.; Fumagalli, L.; Paolorossi, F.; Rovelli, F.; Roselli, M.G.; Maestroni, G.J. Anticancer neuroimmunomodulation by pineal hormones other than melatonin: Preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin. J. Biol. Regul. Homeost. Agents 1997, 11, 119–122. [Google Scholar]
  133. Vijayalaxmi, T.C.R., Jr; Reiter, R.J.; Herman, T.S. Melatonin: From basic research to cancer treatment clinics. J. Clin. Oncol. 2002, 20, 2575–2601. [Google Scholar]
  134. Bartsch, C.; Bartsch, H.; Karasek, M. Melatonin in clinical oncology. Neuro Endocrinol. Lett 2002, 23, 30–38. [Google Scholar]
  135. Jung, B.; Ahmad, N. Melatonin in cancer management: Progress and promise. Cancer Res 2006, 66, 9789–9793. [Google Scholar]
  136. Grant, S.G.; Melan, M.A.; Latimer, J.J.; Witt-Enderby, P.A. Melatonin and breast cancer: Cellular mechanisms, clinical studies and future perspectives. Expert Rev. Mol. Med 2009, 11, e5. [Google Scholar]
  137. Schernhammer, E.S.; Giobbie-Hurder, A.; Gantman, K.; Savoie, J.; Scheib, R.; Parker, L.M.; Chen, W.Y. A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers. Cancer Causes Control 2012, 23, 609–616. [Google Scholar]
  138. Di Bella, L. Physiological basis for a rational therapy of bone marrow diseases. Presented at XVIth International Congress of Hematology, Kyoto, Japan, 5–11 September 1976.
  139. Mediavilla, M.D.; Sanchez-Barcelo, E.J.; Tan, D.X.; Manchester, L.; Reiter, R.J. Basic mechanisms involved in the anti-cancer effects of melatonin. Curr. Med. Chem 2010, 17, 4462–4481. [Google Scholar]
  140. Di Bella, L.; Gualano, L.; Bruschi, C.; Minuscoli, S.; Tarozzi, G. Cytochalasin B influence on megakaryocyte patch-clamp. Adv. Exp. Med. Biol 1999, 460, 373–376. [Google Scholar]
  141. Lee, Y.J.; Tsai, C.H.; Hwang, J.J.; Sheu, T.; Keng, P.C. Involvement of a p53-independent and post-ttranscriptional up-regulation for p21WAF/CIP1 following destabilization of the actin cytoskeleton. Int. J. Oncol 2009, 34, 581–589. [Google Scholar]
  142. Goldberger, R.F.; Epstein, C.J.; Anfinsen, C.B. Purification and properties of a microsomal enzyme system catalyzing the reactivation of reduced ribonuclease and lysozyme. J. Biol. Chem 1964, 239, 1406–1410. [Google Scholar]
  143. Anfinsen, C.B.; Redfield, R.R. Protein structure in relation to function and biosynthesis. Adv. Protein Chem 1956, 11, 1–100. [Google Scholar]
  144. Anfinsen, C.B. The tertiary structure of ribonuclease. Brookhaven Symp. Biol 1962, 15, 184–198. [Google Scholar]
  145. Ellis, R.J. Chaperonins. Curr. Biol 1999, 9, R352. [Google Scholar]
  146. Ellis, R.J. Protein folding: importance of the Anfinsen cage. Curr. Biol 2003, 13, R881–R883. [Google Scholar]
  147. Davis, S.; Mirick, D.K. Residential magnetic fields, medication use, and the risk of breast cancer. Epidemiology 2007, 18, 266–269. [Google Scholar]
  148. Davis, S.; Mirick, D.K.; Chen, C.; Stanczyk, F.Z. Night shift work and hormone levels in women. Cancer Epidemiol. Biomarkers Prev 2012, 21, 609–618. [Google Scholar]
  149. Di Bella, G. Complete objective response to biological therapy of plurifocal breast carcinoma. Neuro. Endocrinol. Lett 2008, 29, 857–866. [Google Scholar]
  150. Di Bella, G. The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer. Neuro Endocrinol. Lett 2011, 32, 751–762. [Google Scholar]
  151. Di Bella, G.; Biagio, C. The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 23 tumors of the head and neck. Neuro Endocrinol Lett 2012, 33, 249–256. [Google Scholar]
  152. Di Bella, L. Presented at First National Conference on Melatonin: From Research to Action, Reggio Calabria, Italy, 25 January 1997.
  153. Di Bella, L. Cancro: Siamo Sulla Strada Giusta? Travel Factory: Roma, Italy, 1997. [Google Scholar]
  154. Richards, M.A.; Stockton, D.; Babb, P.; Coleman, M.P. How many deaths have been avoided through improvements in cancer survival? BMJ 2000, 320, 895–898. [Google Scholar]
  155. Morgan, G.; Ward, R.; Barton, M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin. Oncol 2004, 16, 549–560. [Google Scholar]
  156. Atra, A.; Gerrard, M.; Hobson, R.; Imeson, J.D.; Ashley, S.; Pinkerton, C.R. Improved cure rate in children with B-cell acute lymphoblastic leukaemia (B-ALL) and stage IV B-cell non-Hodgkin’s lymphoma (B-NHL)—Results of the UKCCSG 9003 protocol. Br. J. Cancer 1998, 77, 2281–2285. [Google Scholar]
  157. Ghesquières, H.; Ferlay, C.; Sebban, C.; Perol, D.; Bosly, A.; Casasnovas, O.; Reman, O.; Coiffier, B.; Tilly, H.; Morel, P.; et al. Long-term follow-up of an age-adapted C5R protocol followed by radiotherapy in 99 newly diagnosed primary CNS lymphomas: A prospective multicentric phase II study of the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Ann. Oncol 2010, 21, 842–850. [Google Scholar]
  158. Sun, Y.; Campisi, J.; Higano, C.; Beer, T.M.; Porter, P.; Coleman, I.; True, L.; Nelson, P.S. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med 2012, 18, 1359–1368. [Google Scholar]
  159. Lagadec, C.; Vlashi, E.; Della Donna, L.; Dekmezian, C.; Pajonk, F. Radiation-induced reprogramming of breast cancer cells. Stem Cells 2012, 30, 833. [Google Scholar]
  160. Norsa, A.; Martino, V. Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status. Cancer Biother. Radiopharm 2007, 22, 50–55. [Google Scholar]
  161. Norsa, A.; Martino, V. Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status. Cancer Biother. Radiopharm 2006, 21, 68–73. [Google Scholar]
  162. Todisco, M. Chronic lymphocytic leukemia: Long-lasting remission with combination of cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH. Cancer Biother. Radiopharm 2009, 24, 353–355. [Google Scholar]
  163. Todisco, M. Low-grade non-Hodgkin lymphoma at advanced stage: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin. Am. J. Ther 2007, 14, 113–115. [Google Scholar]
  164. Todisco, M. Relapse of high-grade non-Hodgkin’s lymphoma after autologous stem cell transplantation: A case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, melatonin, retinoids, and ACTH. Am. J. Ther 2006, 13, 556–557. [Google Scholar]
  165. Todisco, M.; Casaccia, P.; Rossi, N. Cyclophosphamide plus somatostatin, bromocriptin, retinoids, melatonin and ACTH in the treatment of low-grade non-Hodgkin’s lymphomas at advanced stage: Results of a phase II trial. Cancer Biother. Radiopharm 2001, 16, 171–177. [Google Scholar]
  166. Di Bella, G. Il Metodo Di Bella; Mattioli: Parma, Italy, 2005. [Google Scholar]
Figure 1. Insoluble in water (A), melatonin (MLT) dissolves in ethyl alcohol. Since absorption and bio-availability are linked with solubility, in the Luigi Di Bella formulation it is combined with a hydrogen bond to adenosine (B), thus becoming perfectly soluble and absorbable, with its biological-functional activities being reinforced. (Copyright Di Bella Foundation).
Figure 1. Insoluble in water (A), melatonin (MLT) dissolves in ethyl alcohol. Since absorption and bio-availability are linked with solubility, in the Luigi Di Bella formulation it is combined with a hydrogen bond to adenosine (B), thus becoming perfectly soluble and absorbable, with its biological-functional activities being reinforced. (Copyright Di Bella Foundation).
Ijms 14 02410f1
Figure 2. Anticancer action of melatonin: main molecular mechanisms. (1) Direct anti-oxidant enzyme activation; (2): bind with ML3 receptor; (3) direct antioxidant activity (scavenger); (4) gene expression regulation (differentiation); (5) calmodulin degradation: antiproliferative; (6) AC inhibition: antiproliferative. ML1/2: melatonin type receptor 1-2; SOD: super oxide dismutase; GRS: glutatione reductase; CAT: catalase; ML3/QR3: melatonin type receptor 3/quinone reductase 2; AC: adenylate ciclase; ROS: reactive oxygen species; RNS: reactive natrium species; AFMK: N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. (Copyright Di Bella Foundation).
Figure 2. Anticancer action of melatonin: main molecular mechanisms. (1) Direct anti-oxidant enzyme activation; (2): bind with ML3 receptor; (3) direct antioxidant activity (scavenger); (4) gene expression regulation (differentiation); (5) calmodulin degradation: antiproliferative; (6) AC inhibition: antiproliferative. ML1/2: melatonin type receptor 1-2; SOD: super oxide dismutase; GRS: glutatione reductase; CAT: catalase; ML3/QR3: melatonin type receptor 3/quinone reductase 2; AC: adenylate ciclase; ROS: reactive oxygen species; RNS: reactive natrium species; AFMK: N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. (Copyright Di Bella Foundation).
Ijms 14 02410f2

Share and Cite

MDPI and ACS Style

Di Bella, G.; Mascia, F.; Gualano, L.; Di Bella, L. Melatonin Anticancer Effects: Review. Int. J. Mol. Sci. 2013, 14, 2410-2430.

AMA Style

Di Bella G, Mascia F, Gualano L, Di Bella L. Melatonin Anticancer Effects: Review. International Journal of Molecular Sciences. 2013; 14(2):2410-2430.

Chicago/Turabian Style

Di Bella, Giuseppe, Fabrizio Mascia, Luciano Gualano, and Luigi Di Bella. 2013. "Melatonin Anticancer Effects: Review" International Journal of Molecular Sciences 14, no. 2: 2410-2430.

Article Metrics

Back to TopTop