[Show abstract][Hide abstract] ABSTRACT: Melatonin, the main secretory product of the pineal gland, is an oncostatic agent that reduces the growth and development of various types of tumors, particularly mammary tumors whose growth is dependent on estrogens. Previous in vivo and in vitro studies point to the hypothesis that melatonin interplays with estrogen signaling pathways at three different levels: i) an indirect mechanism, by interfering with the hypothalamic-pituitary-reproductive axis in such way that the level of plasma estrogens synthesized by the gonadal glands are downregulated; ii) a direct mechanism of the pineal gland at the cell cancer level, disrupting the activation of estradiol receptors, therefore behaving as a selective estrogen receptor modulator; and iii) by regulating the enzymes involved in the biosynthesis of estrogens in other tissues, thus behaving as a selective estrogen enzyme modulator. The intratumoral metabolism and synthesis of estrogens, as a result of the interactions of various enzymes, is more important than blood uptake to maintain mammary gland estrogen levels in menopausal females. Additionally, estrogens are considered to play an important role in the pathogenesis and development of hormone-dependent breast carcinoma. Paracrine interactions among malignant epithelial cells and proximal adipose and endothelial cells, through cytokines and growth factors produced by breast tumor cells, modulate estrogen production at the mammary tumor level and, as a consequence, the genesis and development of mammary tumors. The aim of the present review is to summarize the recent findings describing the mechanisms by which melatonin is able to modulate the crosstalk among malignant epithelial, endothelial and adipose cells in breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Melatonin and progesterone levels decline during the perimenopause. Both hormones inhibit estrogen action and endometrial cancer, but little is known about how they act in combination. Therefore, the interplay of progesterone (P4) and melatonin was investigated in intact female mice.
Three P4 doses, low (25mg), mid (50mg), and high (100mg), combined with 0.5mg 17β-estradiol (E), were administered in the diet (per 1800kcal) for 30 days. Hormone therapy (HT) with the low P4 dose (estradiol/low progesterone replacement therapy (EPLRT)) was used to create an excess estrogen environment to mimic perimenopause. Half the mice were treated with melatonin (M) 15mg/L in the drinking water at night.
The unbalanced EPLRT treatment increased estrogen-regulated responses. Specifically, mice treated with EPLRT had significantly higher levels of ovarian aromatase mRNA versus control, which was prevented in the presence of higher doses of P4 and/or the addition of melatonin. The number of days in estrus also increased in EPLRT-treated versus control mice with no change in the length or number of complete estrous cycles. Melatonin, combined with all doses of P4, increased the number of days spent in estrus, but not the length or number of estrous cycles compared to melatonin alone; however, two-way ANOVA revealed a significant interaction between melatonin and P4 dose for days in estrus and for number of cycles. Although none of the E2 and P4 combinations significantly affected uterine weight compared to control, melatonin addition to the low or mid P4 HT resulted in slightly higher uterine weights compared to melatonin-treated mice. Melatonin significantly increased uterine estrogen receptor alpha (ERα) and progesterone receptor A levels compared to control animals. HT, added in combination with melatonin, reduced ERα levels back to control levels, but PR levels remained elevated albeit intermediary to those achieved with melatonin alone.
The findings that melatonin supplementation inhibits ovarian aromatase expression and increases uterine receptors in mice given an HT that mimics perimenopause may have important clinical applications for the improvement of menopause-related conditions, like menorrhagia, associated with high levels of E2 and low levels of P4.
European journal of obstetrics, gynecology, and reproductive biology 12/2013; 174(1). DOI:10.1016/j.ejogrb.2013.11.027 · 1.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial cells represent one of the critical cellular elements in tumor microenvironment playing a crucial role in the growth and progression of cancer through controlling angiogenesis. Vascular endothelial growth factor (VEGF) produced from tumor cells is essential for the expansion of breast cancer and may function in both paracrine and autocrine manners to promote proliferation, growth, survival and migration of endothelial cells. Since melatonin regulates tumor microenvironment by decreasing the secretion of VEGF by malignant epithelial cells and also regulates VEGF expression in human breast cancer cells, the aim of the present study was to investigate the anti-angiogenic activity of melatonin against the pro-angiogenic effects of breast cancer cells. In this work, we demonstrate that melatonin strongly inhibited the proliferation as well as invasion/migration of human umbilical vein endothelial cells (HUVEC). Melatonin disrupted tube formation and counteracted the VEGF-stimulated tubular network formation by HUVEC. In addition, conditioned media collected from human breast cancer cells were angiogenically active and stimulated tubule length formation and this effect was significantly counteracted by the addition of anti-VEGF or melatonin. Melatonin also disintegrated preformed capillary network. All these findings demonstrate that melatonin may play a role in the paracrine interactions that take place between malignant epithelial cells and proximal endothelial cells. Melatonin could be important in reducing endothelial cells proliferation, invasion, migration and tube formation, through a downregulatory action on VEGF. Taken together, our findings suggest that melatonin could potentially be beneficial as an antiangiogenic agent in breast cancer with possible future clinical applications.
Microvascular Research 03/2013; 87. DOI:10.1016/j.mvr.2013.02.008 · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens. The presence of aromatase on endothelial cells indicates that endothelial cells may contribute to tumor growth by producing estrogens. Since human umbilical vein endothelial cells (HUVECs) express both aromatase and melatonin receptors, the aim of the present study was to evaluate the ability of melatonin to regulate the activity and expression of aromatase on endothelial cells, thus, modulating local estrogen biosynthesis. In the present study, we demonstrated that melatonin inhibits the growth of HUVECs and reduces the local biosynthesis of estrogens through the downregulation of aromatase. These results are supported by three lines of evidence. Firstly, 1 mM of melatonin counteracted the testosterone-induced cell proliferation of HUVECs, which is dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. Secondly, we found that 1 mM of melatonin reduced the aromatase activity of HUVECs. Finally, by real‑time RT-PCR, we demonstrated that melatonin significantly downregulated the expression of aromatase as well as its endothelial-specific aromatase promoter region I.7. We conclude that melatonin inhibits aromatase activity and expression in HUVECs by regulating gene expression of specific aromatase promoter regions, thereby reducing the local production of estrogens.
[Show abstract][Hide abstract] ABSTRACT: Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen-signaling pathways. Melatonin reduces estrogen biosynthesis in human breast cancer cells, surrounding fibroblasts and peritumoral endothelial cells by regulating cytokines that influence tumor microenvironment. This hormone also exerts antiangiogenic activity in tumoral tissue. In this work, our objective was to study the role of melatonin on the regulation of the vascular endothelial growth factor (VEGF) in breast cancer cells. To accomplish this, we cocultured human breast cancer cells (MCF-7) with human umbilical vein endothelial cells (HUVECs). VEGF added to the cultures stimulated the proliferation of HUVECs and melatonin (1 mm) counteracted this effect. Melatonin reduced VEGF production and VEGF mRNA expression in MCF-7 cells. MCF-7 cells cocultured with HUVECs stimulated the endothelial cells proliferation and increased VEGF levels in the culture media. Melatonin counteracted both stimulatory effects on HUVECs proliferation and on VEGF protein levels in the coculture media. Conditioned media from MCF-7 cells increased HUVECs proliferation, and this effect was significantly counteracted by anti-VEGF and 1 mm melatonin. All these findings suggest that melatonin may play a role in the paracrine interactions between malignant epithelial cells and proximal endothelial cells through a downregulatory action on VEGF expression in human breast cancer cells, which decrease the levels of VEGF around endothelial cells. Lower levels of VEGF could be important in reducing the number of estrogen-producing cells proximal to malignant cells as well as decreasing tumoral angiogenesis.
Journal of Pineal Research 08/2012; 54(4). DOI:10.1111/jpi.12007 · 9.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Recent Patents on Endocrine Metabolic & Immune Drug Discovery 02/2012; 6(2):108-16. DOI:10.2174/187221412800604581
[Show abstract][Hide abstract] ABSTRACT: Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen signaling pathways. Melatonin inhibits aromatase enzyme in breast cancer cells and fibroblasts. In addition, melatonin stimulates the adipogenic differentiation of fibroblasts. Our objective was to study whether melatonin interferes in the desmoplastic reaction by regulating some factors secreted by malignant cells, tumor necrosis factor (TNF)-α, interleukin (IL)-11, and interleukin (IL)-6. To accomplish this, we co-cultured 3T3-L1 cells with MCF-7 cells. The addition of breast cancer cells to the co-cultures inhibited the differentiation of 3T3-L1 preadipocytes to mature adipocytes, by reducing the intracytoplasmic triglyceride accumulation, an indicator of adipogenic differentiation, and also stimulated their aromatase activity. Melatonin counteracted the inhibitory effect on adipocyte differentiation and aromatase activity induced by MCF-7 cells in 3T3-L1 cells. The levels of cytokines in the co-culture media were 10 times those found in culture of 3T3-L1 cells alone. Melatonin decreased the concentrations of cytokines in the media and counteracted the stimulatory effect induced by MCF-7 cells on the cytokine levels. One millimolar melatonin induced a reduction in TNF-α, IL-6, and IL-11 mRNA expression in MCF-7 and 3T3-L1 cells. The findings suggest that melatonin may play a role in the desmoplastic reaction in breast cancer through a downregulatory action on the expression of antiadipogenic cytokines, which decrease the levels of these cytokines. Lower levels of cytokines stimulate the differentiation of fibroblasts and decrease both aromatase activity and expression, thereby reducing the number of estrogen-producing cells proximal to malignant cells.
Journal of Pineal Research 11/2011; 52(3):282-90. DOI:10.1111/j.1600-079X.2011.00940.x · 9.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin inhibits the genesis and growth of breast cancer by interfering at different levels in the estrogen-signaling pathways. Melatonin inhibits aromatase activity and expression in human breast cancer cells, thus behaving as a selective estrogen enzyme modulator. As the adipose tissue adjacent to the tumor seems to account for most aromatase expression and enzyme activity in breast tumors and also mediates the desmoplastic reaction or accumulation of undifferentiated fibroblasts around malignant epithelial cells, in this work, we studied the effects of melatonin on the conversion of preadipocytes (3T3-L1) into adipocytes and on the capability of these cells to synthesize estrogens by regulating the expression and enzyme activity of aromatase, one of the main enzymes that participates in the synthesis of estrogens in the peritumoral adipose tissue. Thus, in both differentiating and differentiated 3T3-L1 adipocytes, high concentrations of melatonin increased intracytoplasmic triglyceride accumulation, an indicator of adipogenic differentiation. Melatonin (1 mm) significantly increased the expression of both CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ, two main regulators of terminal adipogenesis, in 3T3-L1 cells. The presence of melatonin during differentiation also induced a parallel reduction in aromatase expression and activity and expression of the cells. The effects of melatonin were reversed by luzindole, a melatonin receptor antagonist, indicating that melatonin acts through known receptor-mediated mechanisms. These findings suggest that, in human breast tumors, melatonin could stimulate the differentiation of fibroblasts and reduce the aromatase activity and expression in both fibroblasts and adipocytes, thereby reducing the number of estrogen-producing cells proximal to malignant cells.
Journal of Pineal Research 05/2011; 52(1):12-20. DOI:10.1111/j.1600-079X.2011.00911.x · 9.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin inhibits the growth of different kinds of neoplasias, especially breast cancer, by interacting with estrogen- responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces sulfatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. In this study, to investigate the in vivo sulfatase-inhibitory properties of melatonin, this indoleamine was administered to ovariectomized rats bearing DMBA-induced mammary tumors, and treated with estrone sulfate. In castrated animals, the growth of estrogen-sensitive mammary tumors depends on the local conversion of biologically inactive estrogens to bioactive unconjugated estrogens. Ovariectomy significantly reduced the size and the number of the tumors while the administration of estrone sulfate to ovariectomized animals stimulated tumor growth, an effect which was suppressed by melatonin. The uterine weight of ovariectomized rats, which depends on the local synthesis of estrogens, was increased by estrone sulfate, except in those animals which were also treated with melatonin. The growth-stimulatory effects of estrone sulfate on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in estrone sulfate-treated rats. Melatonin counteracted the stimulatory effects of estrone sulfate on sulfatase activity and expression and incubation with melatonin decreased the sulfatase activity of tumors from control animals. Animals treated with melatonin had the same survival probability as the castrated animals and it was significantly higher than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by down-regulating the sulfatase pathway of the tumoral tissue.
Current Cancer Drug Targets 04/2010; 10(3):279-286. DOI:10.2174/156800910791190201 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin interacts with estradiol at the estrogen receptor level in different kinds of neoplasias and also regulates the expression and the activity of some enzymes involved in the biosynthesis of estrogens in peripheral tissues. Glioma cells express estrogen receptors and have the ability to synthesize estrogens locally. Since melatonin inhibits the growth of C6 cells, and this indoleamine has been demonstrated to be capable of decreasing aromatase expression and activity in these cells, the aim of the present study was to analyze whether the regulation of the sulfatase, the enzyme that catalyzes the rate-limiting step in the conversion of estrogen sulfates to estrogens, and 17beta-hydroxysteroid dehydrogenase, the enzyme which converts the relatively inactive estrone to the most potent 17beta-estradiol, could be involved in the inhibition of glioma cell growth by melatonin. We found that melatonin decreases the growth of C6 glioma cells and reduces the sulfatase and 17beta-hydroxysteroid dehydrogenase activity. Finally, we demonstrated that melatonin downregulates sulfatase and 17beta-hydroxysteroid dehydrogenase mRNA steady state levels in these glioma cells. By analogy to the implications of these enzymes in other forms of estrogen-sensitive tumors, it is conceivable that their modulation by melatonin may play a role in the growth of glioblastomas.
[Show abstract][Hide abstract] ABSTRACT: Melatonin inhibits the growth of different kinds of neoplasias, especially breast cancer, by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces sulfatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. In this study, to investigate the in vivo sulfatase-inhibitory properties of melatonin, this indoleamine was administered to ovariectomized rats bearing DMBA-induced mammary tumors, and treated with estrone sulfate. In castrated animals, the growth of estrogen-sensitive mammary tumors depends on the local conversion of biologically inactive estrogens to bioactive unconjugated estrogens. Ovariectomy significantly reduced the size and the number of the tumors while the administration of estrone sulfate to ovariectomized animals stimulated tumor growth, an effect which was suppressed by melatonin. The uterine weight of ovariectomized rats, which depends on the local synthesis of estrogens, was increased by estrone sulfate, except in those animals which were also treated with melatonin. The growth-stimulatory effects of estrone sulfate on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in estrone sulfate-treated rats. Melatonin counteracted the stimulatory effects of estrone sulfate on sulfatase activity and expression and incubation with melatonin decreased the sulfatase activity of tumors from control animals. Animals treated with melatonin had the same survival probability as the castrated animals and significantly higher than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by down-regulating the sulfatase pathway of the tumoral tissue.
Current cancer drug targets 04/2010; 10(3):279-86. · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin reduces the development of breast cancer interfering with oestrogen-signalling pathways, and also inhibits aromatase activity and expression. Our objective was to study the promoters through which melatonin modifies aromatase expression, evaluate the ability of melatonin to regulate cyclooxygenases and assess whether the effects of melatonin are related to its effects on intracellular cAMP, in MCF-7 cells.
Total aromatase mRNA, aromatase mRNA promoter regions and cyclooxygenases mRNA expression were determined by real-time RT-PCR. PGE(2) and cAMP were measured by kits.
Melatonin downregulated the gene expression of the two major specific aromatase promoter regions, pII and pI.3, and also that of the aromatase promoter region pI.4. Melatonin 1 nM was able to counteract the stimulatory effect of tetradecanoyl phorbol acetate on PGE(2) production and inhibit COX-2 and COX-1 mRNA expression. Melatonin 1 nM elicited a parallel time-dependent decrease in both cyclic AMP formation and aromatase mRNA expression.
This study shows that melatonin inhibits aromatase activity and expression by regulating the gene expression of specific aromatase promoter regions. A possible mechanism for these effects would be the regulation by melatonin of intracellular cAMP levels, mediated by an inhibition of cyclooxygenase activity and expression.
British Journal of Cancer 09/2009; 101(9):1613-9. DOI:10.1038/sj.bjc.6605336 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin exerts oncostatic effects on different kinds of tumors, especially on hormone-dependent breast cancer. The general conclusion is that melatonin, in vivo, reduces the incidence and growth of chemically-induced mammary tumors in rodents, and, in vitro, inhibits the proliferation and invasiveness of human breast cancer cells. Both studies support the hypothesis that melatonin inhibits the growth of breast cancer by interacting with estrogen-signaling pathways through three different mechanisms: (a) the indirect neuroendocrine mechanism which includes the melatonin down-regulation of the hypothalamic-pituitary-reproductive axis and the consequent reduction of circulating levels of gonadal estrogens, (b) direct melatonin actions at tumor cell level by interacting with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator (SERM), and (c) the regulation of the enzymes involved in the biosynthesis of estrogens in peripheral tissues, thus behaving as a selective estrogen enzyme modulator (SEEM). As melatonin reduces the activity and expression of aromatase, sulfatase and 17beta-hydroxysteroid dehydrogenase and increases the activity and expression of estrogen sulfotransferase, it may protect mammary tissue from excessive estrogenic effects. Thus, a single molecule has both SERM and SEEM properties, one of the main objectives desired for the breast antitumoral drugs. Since the inhibition of enzymes involved in the biosynthesis of estrogens is currently one of the first therapeutic strategies used against the growth of breast cancer, melatonin modulation of different enzymes involved in the synthesis of steroid hormones makes, collectively, this indolamine an interesting anticancer drug in the prevention and treatment of estrogen-dependent mammary tumors.
Current cancer drug targets 01/2009; 8(8):691-702. DOI:10.2174/156800908786733469 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cadmium (Cd) is a human carcinogen present in tobacco smoke and contaminated industrial soils. Metallothioneins (MTs) are intracellular proteins involved in protecting against Cd. The toxic effects of Cd can be modified by compounds able to modulate MTs synthesis. Melatonin has oncostatic properties and has also been shown to counteract the toxic effects of Cd. In this study we examine the possible role of melatonin in Cd-induced expression of several MT isoforms (MT-2A, MT-1X, MT-1F and MT-1E) in three human tumor cell lines (MCF-7, MDA-MB-231 and HeLa). We found that, in all cell types, melatonin increases Cd-induced expression of MT-2A, which is considered to protect against Cd toxicity. As regards MT-1 subtypes, which have been related with cell invasiveness and high histological grade tumors, melatonin caused Cd-induced expression in both breast cancer cell lines to decrease. These effects point towards melatonin's possible role as a preventive agent for carcinogenesis dependent on Cd contamination.
[Show abstract][Hide abstract] ABSTRACT: The goal was to evaluate whether melatonin (Mel) down-regulates hTERT expression induced by 17beta-estradiol (E(2)) or cadmium (Cd) in breast cancer cells. We found that: (a) Mel inhibits E(2) or Cd-induced hTERT transcription in hTERT-Luc transfected MCF-7 cells, (b) Mel significantly reduces E(2)- and Cd-mediated hTERT transactivation triggered by ERalpha in transfected HeLa cells, (c) Mel inhibits hTERT expression induced by E(2) or Cd in MCF-7 cells. Melatonin inhibition of telomerase activity supports a possible role in treatment of estrogen-dependent tumors or carcinogenesis by environmental or occupational exposure to xenoestrogens.
Cancer letters 06/2008; 268(2):272-7. DOI:10.1016/j.canlet.2008.04.001 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on estrogen-dependent mammary tumors. Current knowledge about the mechanisms by which melatonin inhibits the growth of breast cancer cells point to an interaction of melatonin with estrogen-responsive pathways. The intratumoral production of estrogens in breast carcinoma tissue plays a pivotal role in the proliferation of mammary tumoral cells and its blockade is one of the main objectives of the treatment of breast cancer. The aim of the present work is centered on the study of the role of melatonin in the control of some enzymes involved in the formation and transformation of estrogens in human breast cancer cells. The present study demonstrates that melatonin, at physiologic concentrations, modulates the synthesis and transformation of biologically active estrogens in MCF-7 cells, through the inhibition of sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) activity and expression, enzymes involved in the estradiol formation in breast cancer cells. Physiologic concentrations of melatonin also stimulate the activity and expression of estrogen sulfotransferase (EST), the enzyme responsible for the formation of the biologically inactive estrogen sulfates. The level of EST mRNA steady-state of cells treated with melatonin was three times higher than that in control cells. These findings which document that melatonin has an inhibitory effect on STS and 17beta-HSD1 and a stimulatory effect on EST, in combination with its previously described antiaromatase effect, can open up new and interesting possibilities in clinical applications of melatonin in breast cancer.
Journal of Pineal Research 03/2008; 45(1):86-92. DOI:10.1111/j.1600-079X.2008.00559.x · 9.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The study in ovariectomized (Ovx) rats, as a model of menopausal status, of the effects of melatonin (M) and/or estradiol (E), associated or not with food restriction, on body weight (BW) and serum leptin levels.
Female SD rats (200-250 g) were Ovx and treated with E, M, E+M or its diluents. Control sham-Ovx rats were treated with E-M diluents. After 7 weeks being fed ad libitum, the animals were exposed for 7 more weeks to a 30% food restriction. We measured: food intake, BW, nocturnal and diurnal urinary excretion of sulphatoxymelatonin (aMT6s), leptin in midday and midnight blood samples, glucose, total cholesterol, LDL, HDL and triglycerides.
Day/night rhythm of aMT6s excretion was preserved in all cases. The increase of aMT6s excretion in M-treated animals basically affected the nocturnal period. In animals fed ad libitum, E fully prevented Ovx-induced increase of BW, leptin and cholesterol. Melatonin reduced food intake and partially prevented the increase of BW and cholesterol, without changing leptin levels. Under food restriction, M was the most effective treatment in reducing BW and cholesterol. Leptin levels were similar in M, E or E+M treated rats, and lower than in untreated Ovx rats.
Our result gives a preliminary experimental basis for a post-menopausal co-treatment with estradiol and melatonin. It could combine the effectiveness of estradiol (not modified by melatonin) with the positive effects of melatonin (improvement of sleep quality, prevention of breast cancer, etc.). The possible beneficial effects of melatonin which could justify its use, need to be demonstrated in clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Melatonin is a pineal hormone which basically acts through membrane receptors, but also as a free radical scavenger (requiring no receptors), and by binding to intracellular sites (calmodulin and nuclear receptors). Membrane receptors (MT1, MT2) are associated to G-proteins linked to inhibition of adenylyl cyclase and decrease of cAMP, and are expressed by almost all structures of the CNS (especially hypothalamic suprachiasmatic nucleus and pars tuberalis of the pituitary), as well as in peripheral tissues (gastrointestinal tract, thymus, smooth muscle of blood vessels, adipocytes, lymphocytes, etc). Among the actions attributed to melatonin are those of antioxidant, controller of circadian rhythms (especially sleep-wake and core body temperature), immunomodulation, antidepressant, etc. This wide spectrum of actions suggests many possible therapeutic applications for melatonin. However, its use as a drug presents some limitations (to optimise pharmacological responses of each subtype or receptors, its rapid metabolic inactivation, etc.) that have caused many laboratories to develop analogues without the above mentioned problems. Two are the patented melatoninergic drugs with more interesting properties: one is ramelteon (US6034239; Rozerem™), approved by the FDA for the long-term treatment of sleep disturbances characterized by difficulty with sleep onset; the second, agomelatine (US5318994; Valdoxan™), which is completing the phase III trial, was designed for the treatment of symptoms of major depressive disorders, particularly anxiety, sleep troubles and circadian disturbances.
Recent Patents on Endocrine Metabolic & Immune Drug Discovery 05/2007; 1(2):142-151. DOI:10.2174/187221407780831984