Emilio J. Sanchez-Barcelo

The objective of this article is to review the basis supporting the usefulness of melatonin as an adjuvant therapy for breast cancer (BC) prevention in several groups of individuals at high risk for this disease. Melatonin, as a result of its antiestrogenic and antioxidant properties, as well as its ability to improve the efficacy and reduce the side effects of conventional antiestrogens, could safely be associated with the antiestrogenic drugs presently in use. In individuals at risk of BC due to night shift work, the light-induced inhibition of melatonin secretion, with the consequent loss of its antiestrogenic effects, would be countered by administering this neurohormone. BC risk from exposure to metalloestrogens, such as cadmium, could be treated with melatonin supplements to individuals at risk of BC due to exposure to this xenoestrogen. The BC risk related to obesity may be reduced by melatonin which decrease body fat mass, inhibits the enhanced aromatase expression in obese women, increases adiponectin secretion, counteracts the oncogenic effects of elevated concentrations of leptin; and decreases blood glucose levels and insulin resistance. Despite compelling experimental evidence of melatonin’s oncostatic actions being susceptible to lowering BC risk, there is still a paucity of clinical trials focused on this subject.

The ubiquitin proteasome system has been proposed as a possible mechanism involved in the multiple actions of melatonin. COP1 (constitutive photomorphogenesis protein 1), a RING finger‐type ubiquitin E3 ligase formerly identified in Arabidopsis, is a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis). In darkness, COP1 binds to photomorphogenic transcription factors driving its degradation via the 26S proteasome; blue light, detected by cryptochromes, and red and far‐red light detected by phytochromes, negatively regulate COP1. Homologues of plant COP1 containing all the structural features present in Arabidopsis as well as E3 ubiquitin ligase activity have been identified in mice and humans. Substrates for mammalian (m) COP1 include p53, AP‐1 and c‐Jun, p27^Kip1, ETV1, MVP, 14‐3‐3σ, C/EBPα, MTA1, PEA3, ACC, TORC2 and FOXO1. This mCOP1 target suggests functions related to tumorigenesis, gluconeogenesis, and lipid metabolism. The role of mCOP1 in tumorigenesis (either as a tumor promoter or tumor suppressor), as well as in glucose metabolism (inhibition of gluconeogenesis) and lipid metabolism (inhibition of fatty acid synthesis), has been previously demonstrated. COP1, along with numerous other ubiquitin ligases, is regulated by the COP9 signalosome; this protein complex is associated with the oxidative stress sensor Keap1 and the deubiquitinase USP15. The objective of this review was to provide new information on the possible role of COP1 and COP9 as melatonin targets. The hypothesis is based on common functional aspects of melatonin and COP1 and COP9, including their dependence on light, regulation of the metabolism, and their control of tumor growth.

This article reviews the more recent patents in three kinds of therapeutic strategies using the application of visible light to irradiate photosensible substances (PSs) of different natures. The light-activation of these PSs is directly responsible for the desired therapeutic effects. This group of light therapies includes photodynamic therapy (PDT), photothermal therapy (PTT) and photoimmunotherapy (PIT). Therapeutic mechanisms triggered by the activation of the PSs depend basically (though not exclusively) on the release of reactive oxygen species (ROS) and the activation of immune responses (PDT and PIT) or the local generation of heat (PTT). The main difference between PIT and PDT is that in PIT, monoclonal antibodies (MABs) are associated to PSs to improve the selective binding of the PSs to the target tissues. All these therapeutic strategies offer the possibility of destroying tumor tissue without damaging the surrounding healthy tissue, which is not achievable with chemotherapy or radiotherapy. PDT is also used as an alternative or adjuvant antimicrobial therapy together with the traditional antibiotic therapy since these organisms are unlikely to develop resistance to the ROS induced by PDT. Furthermore, PDT also induces an immune response against bacterial pathogens. The current challenge in PDT, PIT and PTT is to obtain the highest level of selectivity to act on targeted sick tissues with the minimum effects on the surrounding healthy tissue. The development of new PSs with high affinity for specific tissues, new PSs- MABs conjugates to bind to specific kinds of tumors, and new light-sensible nanoparticles with low toxicity, will increase the clinical utility of these therapies.

The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of theirCNSdue to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age‐related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration inTSmice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed inTSmice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition inTSmice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampalLTPin trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus ofTSmice. These results indicate that the cognitive‐enhancing effects of melatonin in adultTSmice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression ofDSneuropathology.

Ts65Dn mice (TS), the most commonly used model of Down syndrome (DS), exhibit phenotypic characteristics of this condition. Both TS mice and DS individuals present cognitive disturbances, age‐related cholinergic degeneration, and increased brain expression of β‐amyloid precursor protein (AβPP). These neurodegenerative processes may contribute to the progressive cognitive decline observed in DS. Melatonin is a pineal indoleamine that has been reported to reduce neurodegenerative processes and improve cognitive deficits in various animal models. In this study, we evaluated the potentially beneficial effects of long‐term melatonin treatment on the cognitive deficits, cholinergic degeneration, and enhanced AβPP and β‐amyloid levels of TS mice. Melatonin was administered for 5 months to 5‐ to 6‐month‐old TS and control (CO) mice. Melatonin treatment improved spatial learning and memory and increased the number of choline acetyltransferase (ChAT)‐positive cells in the medial septum of both TS and CO mice. However, melatonin treatment did not significantly reduce AβPP or β‐amyloid levels in the cortex or the hippocampus of TS mice. Melatonin administration did reduce anxiety in TS mice without inducing sensorimotor alterations, indicating that prolonged treatment with this indoleamine is devoid of noncognitive behavioral side effects (e.g., motor coordination, sensorimotor abilities, or spontaneous activity). Our results suggest that melatonin administration might improve the cognitive abilities of both TS and CO mice, at least partially, by reducing the age‐related degeneration of basal forebrain cholinergic neurons. Thus, chronic melatonin supplementation may be an effective treatment for delaying the age‐related progression of cognitive deterioration found in DS.

The usefulness of melatonin and melatoninergic drugs in breast cancer therapy is based on its Selective Estrogen Receptor Modulator (SERM) and Selective Estrogen Enzyme Modulator (SEEM) properties. Because of the oncostatic properties of melatonin, its nocturnal suppression by light-at-night (LAN) has been considered a risk-factor for breast cancer. Melatonin’s SERM actions include modulation of estrogen-regulated cell proliferation, invasiveness and expression of proteins, growth factors and proto-oncogenes (hTERT, p53, p21, TGFβ, E-cadherin, etc.). These actions are observable with physiologic doses of melatonin only in cells expressing ERα, and mediated by MT1 melatonin receptors. Melatonin acts like a SEEM, inhibiting expression and activity of P450 aromatase, estrogen sulfatase and type 1, 17β- hydroxysteroid dehydrogenase, but stimulating that of estrogen sulfotransferase. This double action mechanism (SERM and SEEM), and the specificity for ERα bestows melatonin with potential advantages for breast cancer treatments, associated with other antiestrogenic drugs, and idea already patented. LAN enhances the growth of rat mammary tumors by decreasing or suppressing melatonin production. Epidemiologic studies have also described increased breast cancer risk in women exposed to LAN. Since the strongest suppression of nocturnal melatonin occurs with wavelength light of the blue spectral region, optical and lightening devices filtering the blue light spectrum have been proposed to avoid the risks of light-induced suppression of nocturnal melatonin.

The possible oncostatic properties of melatonin on different types of neoplasias have been studied especially in hormone-dependent adenocarcinomas. Despite the promising results of these experimental investigations, the use of melatonin in breast cancer treatment in humans is still uncommon. This article reviews the usefulness of this indoleamine for specific aspects of breast cancer management, particularly in reference to melatonin's antiestrogenic and antioxidant properties: i) treatments oriented to breast cancer prevention, especially when the risk factors are obesity, steroid hormone treatment or chronodisruption by exposure to light at night (LAN); ii) treatment of the side effects associated with chemo- or radiotherapy. The clinical utility of melatonin depends on the appropriate identification of its actions. Because of its SERM (selective estrogen receptor modulators) and SEEM (selective estrogen enzyme modulators) properties, and its virtual absence of contraindications, melatonin could be an excellent adjuvant with the drugs currently used for breast cancer prevention (antiestrogens and antiaromatases). The antioxidant actions also make melatonin a suitable treatment to reduce oxidative stress associated with chemotherapy, especially with anthracyclines, and radiotherapy.

This study analyzes the results of clinical trials of treatments with melatonin conducted in children, mostly focused on sleep disorders of different origin. Melatonin is beneficial not only in the treatment of dyssomnias, especially delayed sleep phase syndrome, but also on sleep disorders present in children with attention-deficit hyperactivity, autism spectrum disorders, and, in general, in all sleep disturbances associated with mental, neurologic, or other medical disorders. Sedative properties of melatonin have been used in diagnostic situations requiring sedation or as a premedicant in children undergoing anesthetic procedures. Epilepsy and febrile seizures are also susceptible to treatment with melatonin, alone or associated with conventional antiepileptic drugs. Melatonin has been also used to prevent the progression in some cases of adolescent idiopathic scoliosis. In newborns, and particularly those delivered preterm, melatonin has been used to reduce oxidative stress associated with sepsis, asphyxia, respiratory distress, or surgical stress. Finally, the administration of melatonin, melatonin analogues, or melatonin precursors to the infants through the breast-feeding, or by milk formula adapted for day and night, improves their nocturnal sleep. Side effects of melatonin treatments in children have not been reported. Although the above-described results are promising, specific studies to resolve the problem of dosage, formulations, and length of treatment are necessary.