Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells
Javier FloridoCésar Rodríguez-SantanaLaura Martinez‐RuizAlba López‐RodríguezDarío Acuña‐CastroviejoIryna RusanovaGermaine Escames
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Abstract:
Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications.Keywords:
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Cell Signaling
Abstract Background: As one of the most common surgeries performed in veterinary medicine, ovariohysterectomy (OHE) can induce stress in dogs. The antioxidant properties of melatonin have been confirmed in various studies. This study aimed to investigate the effects of melatonin administration on oxidative stress in dogs before and after OHE. In this study, 25 mature female intact dogs were selected and randomly divided into five equal groups: Melatonin, OHE, melatonin+OHE+melatonin, melatonin+anesthesia+melatonin, and control groups. Melatonin (0.3 mg/Kg/day, p.o.) was administrated to the dogs in the melatonin, melatonin+OHE+melatonin, and melatonin+anesthesia+melatonin groups on days -1, 1, 2, and 3 (day 0=OHE). Blood sampling was performed on days -1, 1, 3, and 5 of the study. Blood samples were immediately transferred to the laboratory and sera were separated and stored at -20 °C. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) concentrations were significantly higher in the melatonin and melatonin+anesthesia+melatonin groups compared to those of the control group. Results: The level of antioxidant enzymes significantly decreased in the OHE group compared to that of other groups. The administration of melatonin increased the level of antioxidant enzymes in ovariohysterectomized dogs. OHE significantly increased the concentration of malondialdehyde (MDA) in comparison to that of other groups. Melatonin administration significantly decreased the level of MDA in intact, anesthetized, and ovariohysterectomized dogs. Conclusions: It can be stated that the administration of melatonin one day before and during one week after OHE could control oxidative stress in dogs with increased antioxidant enzymes and decreased MDA levels.
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Continuous light or darkness has various effects on different systems. In the present research work, the effects of constant light and darkness exposure of male rats and oral administration of exogenous melatonin on the serum levels of melatonin have been studied.Thirty adult male Wistar rats were divided into six groups of: (1) Control, (2) melatonin, (3) light, (4) light and melatonin, (5) darkness, and (6) darkness and melatonin. All groups were placed according to light conditions for 10 days. Melatonin was administered orally after a period of 10 days to Groups 2, 4, and 6 (10 mg/kg of body weight). Serum levels of melatonin were measured using ELISA.The results showed the significant difference on serum melatonin in darkness, no light, and control groups. Although serum levels of melatonin were different in melatonin groups, the difference is not significant.We concluded that being exposed to continuous darkness leads to an increase in serum melatonin.
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In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism.In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose.In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%.We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.
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Science ’s STKE focuses on the signaling pathways activated in response to pathological accumulation of reactive oxygen species (ROS), as well as on mechanisms by which cells have harnessed these reactive molecules as active participants in signaling that leads to a desirable cellular response. ROS are chemically reactive because they contain unpaired electrons and, depending on the location of their production and the molecules with which they interact, they can cause cellular damage or trigger specific signaling events. Indeed, kinases and phosphatases are now recognized as key molecules that can be modified by interaction with ROS, and the Protocol by Wu and Terada describes a method for detecting oxidatively modified protein tyrosine phosphatases. In a Perspective, Michel et al . discuss how susceptibility to elevated ROS contributes to death of specific neurons and in a Review, Storz discusses the signaling pathways activated to detoxify ROS and how mitochondrial ROS may contribute to aging.
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Melatonin has been proposed as a potent anti-oxidant, and its presence in many plants and foods has been suggested to be beneficial for health. Indeed, the concentrations of melatonin in blood and the melatonin metabolite 6 sulphatoxymelatonin in urine have been found to increase significantly after ingestion of melatonin-rich foods. In this review, the studies have been critically evaluated in light of the reported plant melatonin concentrations and our knowledge of pharmacokinetics of orally administered pure melatonin. In the case of studies involving measurement of plasma melatonin following ingestion of beer or fruits, the reported increase in melatonin is not consistent with the amount of melatonin ingested. Similarly, the amount of melatonin metabolite excreted following ingestion of melatonin-rich foods greatly exceeded the amount of melatonin ingested. It is concluded that studies reporting the appearance of melatonin in blood and its metabolites in urine following ingestion of melatonin-rich foods are flawed. While there may be health benefits for certain foods, it is difficult to accept that these are due to their low melatonin content.
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Mitochondria are the main source of reactive oxygen species in the cell. These reactive oxygen species have long been known as being involved in oxidative stress. This is a review of the mechanisms involved in reactive oxygen species generation by the respiratory chain and some of the dehydrogenases and the control by thermodynamic and kinetic constraints. Mitochondrial ROS produced at the level of the bc1 complex as well at the level of complex I are discussed. It was recognized more than a decade ago that they can also function as signaling molecules. This signaling role will be developed both in terms of mechanism and in terms of mitochondrial ROS signaling. The notion that hydrogen peroxide acts not only as a damaging oxidant but also as a signaling molecule was proposed more than a decade ago. Hydrogen peroxide signaling can be either direct (oxidation of its target) or indirect (involving peroxiredoxins, for example). The consequences of ROS signaling on crucial biologic processes such as cell proliferation and differentiation are discussed.
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The goal of this study was to determine the effect of oral melatonin in divided doses on plasma melatonin levels in patients with metastatic melanoma. Hourly blood samples were obtained from five patients for 24 h prior to melatonin administration and for 24 h during oral administration of melatonin, 50 mg every 4 h. In two of the five patients, the expected nocturnal plasma melatonin peak was observed. Oral melatonin was well absorbed. Plasma melatonin levels exhibited six peaks and troughs, were two to four-fold higher during peaks than troughs, and remained more than 25 times higher than peak pretreatment melatonin levels, even during troughs. Divided oral doses of melatonin were well tolerated and maintained plasma melatonin levels 25-80 times higher than endogenous peak values.
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Melatoninの臨床的意義は未だ不明である.著者らは肝硬変症22例,慢性肝炎11例,急性肝炎4例,慢性腎不全9例,各種内分泌疾患52例および健常者41例を対象とし,血清melatonin濃度をRIAにて測定し臨床的検討を加えた.その結果,肝硬変症および急性肝炎患者における血清melatoninの昼間基礎値は全例高値を示した.また,肝硬変症患者においても健常者と同様の夜間に増加する血清melatoninの日内リズムを認めた.血清melatoninの昼間基礎値はICG15分停滞率および血清総ビリルビン濃度と有意の正相関を示した.血中からのmelatoninクリアランスは2相性を示し,肝硬変症患者における血中半減期は健常者に比較して有意の遅延を示した.以上の成績より,肝機能障害時における血清melatoninの昼間基礎値の上昇機序は,肝でのmelatonin代謝クリアランス速度の遅延によると考えられ,肝機能障害の程度の判定の臨床的指標として有用であると考えられる.
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