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Towards rational and evidence-based use of melatonin in prostate cancer prevention and treatment
Abstract
Prostate cancer is a public health problem of the elderly men. It has been estimated that one in six men will develop prostate cancer in his lifetime in the USA. There is thus a huge clinical demand for effective therapies for the prevention and treatment of the disease. Here, the scientific evidence supporting the effectiveness of melatonin in inhibiting the development and progression of prostate cancer is reviewed. The rational use of melatonin in prostate cancer prevention, stabilization of clinically localized favourable-risk prostate cancer and palliative treatment of advanced or metastatic tumour is discussed within the context of the molecular pathogenesis of the disease.
... Melatonin (MLT) is a pleiotropic hormone with antioxidant properties that regulate mitochondrial activity [6][7][8][9][10] and has been investigated as a PCa suppressor [11]. Patients with PCa exhibit low MLT serum levels when compared to healthy individuals, with a notable decrease when benign prostatic hyperplasia (BPH) progresses to adenocarcinoma [11,12]. ...
... Melatonin (MLT) is a pleiotropic hormone with antioxidant properties that regulate mitochondrial activity [6][7][8][9][10] and has been investigated as a PCa suppressor [11]. Patients with PCa exhibit low MLT serum levels when compared to healthy individuals, with a notable decrease when benign prostatic hyperplasia (BPH) progresses to adenocarcinoma [11,12]. Most cases of PCa (75%) are diagnosed in men over 65 years [11], coincidental to the period when MLT synthesis is reduced [13] and mitochondrial dysfunction increases due to ROS production [14,15]. ...
... Patients with PCa exhibit low MLT serum levels when compared to healthy individuals, with a notable decrease when benign prostatic hyperplasia (BPH) progresses to adenocarcinoma [11,12]. Most cases of PCa (75%) are diagnosed in men over 65 years [11], coincidental to the period when MLT synthesis is reduced [13] and mitochondrial dysfunction increases due to ROS production [14,15]. Regarding this evidence, MLT supplementation in patients within risk age of PCa (30-40 years old) may be an interesting chemoprevention strategy [16]. ...
Prostate cancer development has been associated with changes in mitochondrial activity and reactive oxygen species (ROS) production. Melatonin (MLT) and docosahexaenoic acid (DHA) have properties to modulate both, but their protective role, mainly at early stages of prostate cancer, remains unclear. In this study, the effects of MLT and DHA, combined or not, on PNT1A cells with regard to mitochondria bioenergetics, ROS production, and proliferation-related pathways were examined. Based on dose response and lipid accumulation assays, DHA at 100 μM and MLT at 1 μM for 48 h were chosen. DHA doubled and MLT reduced (40%) superoxide anion production, but coincubation (DM) did not normalize to control. Hydrogen peroxide production decreased after MLT incubation only (p
... MLT is a pineal hormone that mainly regulates the circadian rhythm of the human (3). Furthermore it may also have anticancer properties in many types of cancers including ovarian cancer (2). ...
... Previous studies have shown that the combination of platinum derivatives with different substances may be an effective therapeutic strategy for the treatment of ovarian cancer (2,(32)(33)(34)(35). Among the compounds tested in combination with cytostatics was MLT, which also exhibited antitumor activity (2,3,36). MLT toxicity of the chemotherapeutic agent on normal ovarian epithelial cells (2). ...
Background/aim:
Melatonin (MLT), through the interaction with membrane melatonin receptors MT1, can improve the effectiveness of cytostatic agents, including cisplatin (CP). The aim of this study was to examine the synergistic effect of MLT and CP in three cell lines: IOSE 364, SK-OV-3 and OVCAR-3, as well as to assess the role of MT1 receptors in this mechanism.
Materials and methods:
Using the SRB assay we investigated the effect of different concentrations of CP and MLT on cell viability. Tests, using luzindole - MT1 inhibitor, allowed us to assess the potential involvement of MT1 in the mechanism of MLT action.
Results:
MLT at certain concentrations demonstrated a synergistic effect in combination with CP. The addition of luzindole did not affect the action of MLT in combination with CP.
Conclusion:
In summary, the synergistic effect of MLT with CP seems to be independent of membrane MT1 receptors.
... Chronic exposure to artificial light at night deregulates melatonin levels, as shown in rodent models and in cohort studies of night-shift workers [14]. In addition, an inverse correlation between melatonin levels and tumor incidence has been reported in prospective nested case control studies [15][16][17][18][19][20][21][22], suggesting that supplementation with melatonin might be proposed as cancer chemopreventive treatment in human clinical studies [23][24][25]. ...
... Many groups, including ours, showed that high levels of endogenous melatonin measured many years before the onset of breast cancer were associated with a reduction of breast cancer occurrence [15,16]. Other sets of evidence suggested a protective role of circulating melatonin on prostate cancer development [17]. ...
Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy.
... In that context , Li et al. (2008) and Jung et al. (2009) reported that melatonin suppressed the formation of pro-inflammatory cytokines such as tumor necrosis factor-(TNF-), interleukin (IL)-1. In addition, Gonzaíez-Puga et al. (2007) and Shiu (2007) demonstrated that the induction of cell death by melatonin in cancer cells had been described in melanoma, neuroblastoma, prostate cancer, breast cancer and colon cancer cells alone or in combination with other compounds. progression, including that of HCC, which was typically characterized by a high level of vascularization (Zachary, 2003). ...
... In line with that, Cui et al. (2006) investigated that melatonin suppressed angiogenesis directly or indirectly and pharmacologic concentrations of melatonin had a direct anti-angiogenic effect through the inhibition of proliferation in the vascular endothelial cell. Our results supported Blask et al. (2005), El-Sokkary et al. (2006) and Shiu (2007) who suggested that melatonin which was an important oncostatic agent, exerted its anti-tumor effect through immunomodulatory, anti-proliferative and anti-oxidant pathways. In addition, Dai et al. (2008) reported that physiologic concentrations of melatonin had no obvious impact on the VEGF expression, whereas pharmacologic concentrations of melatonin suppress the VEGF, mRNA and protein levels induced by hypoxia mimetic cobalt chloride (CoCl 2 ). ...
2-Nitropropane (2-NP) is suggested to be a human carcinogen, a genotoxicant and hepatocarcinogen in rodents. The present study was designed to evaluate the role of melatonin (Mel) as an anticancerous agent in hepatocellular carcinoma (HCC) induced by 2-NP. Forty eight male Swiss albino mice were divided into 5 groups. Group I, II and III served as controls. Group IV was injected IP with 2-NP every other day for 14 weeks. Group V was injected IP with melatonin 30 min prior to 2-NP injection. Mice were sacrificed after 4, 8 and 14 weeks. Histopathological results showed poorly differentiated HCC; pleomorphic atypical hepatocytes after 8 weeks of receiving 2-NP. Proliferating streaks and cords of malignant hepatocytes were prominent after 14 weeks of 2-NP injection. (Mel + 2-NP) treatment revealed histological features more or less similar to normal control with dilated sinusoids, evidence of apoptosis, eosinophilic cytoplasm, few large necrotic cells, microsteatosis and well defined Kupffer cells. Histochemically, group IV showed continuous decrease in catalase activity and very weak activity was reached after 14 weeks. In group V, marked and moderate catalase activity was observed after 4 and 8 weeks, respectively as well as marked diffused reaction after 14 weeks. Immunohistochemically, PCNA and VEGF expressions were significantly increased in group IV and this increment was time dependant. Decreased numbers of PCNA and VEGF expressions in group V were seen as compared with their counterparts. It was concluded that 2-NP was a hepatocellular carcinogen in mice and melatonin exerted its anticancerous role through its antiproliferative and antiangiogenic effects.
... As a consequence, there is a significant clinical demand for new therapies for the prevention and treatment of the disease. Importantly, melatonin has been shown by a wealth of epidemiological and clinical studies to be a potential prostate tumor oncostatic hormone [2,3], which is of promise for further development as a novel anti-prostate cancer therapeutic agent. While other laboratories have reported various receptor-independent inhibitory effects of melatonin on prostate cancer growth [4][5][6][7][8][9], our group has demonstrated, in a series of studies, an antiproliferative action of melatonin on androgen receptor (AR)-positive prostate cancer cells which is transduced via the membrane G protein-coupled MT 1 receptor [10][11][12][13][14]. Stimulation of MT 1 receptors by melatonin inhibits the proliferation of AR-positive transformed and malignant prostate epithelial cells by up-regulating p27 Kip1 gene and protein expression through dual activation of Ga s /protein kinase A (PKA) and Ga q /protein kinase C (PKC) in parallel [15]. ...
... Furthermore, melatoninÕs up-regulatory effects on p27 Kip1 gene transcription, as reflected by stimulation of p27 Kip1 promoter activities and its inhibitory effects on LNCaP and 22Rv1 prostate cancer cell proliferation, are abrogated by NF-jB activator but mimicked by NF-jB inhibitor (Figs. 4 and 5). Taken together with our previous findings on the MT 1 receptor-mediated antiproliferative signaling pathway in AR-positive prostate epithelial cells [3,[13][14][15][16], the present data suggest that inhibition of constitutively active NF-jB via melatonin MT 1 receptorinduced dual activation of (Ga s ) PKA and (Ga q ) PKC can de-repress the p27 Kip1 promoter leading to transcriptional up-regulation of p27 Kip1 . ...
Our laboratory has recently demonstrated a melatonin MT(1) receptor-mediated antiproliferative signaling mechanism in androgen receptor (AR)-positive prostate epithelial cells which involves up-regulation of p27(Kip1) through dual activation of Gα(s) /protein kinase A (PKA) and Gα(q) /protein kinase C (PKC) in parallel, and down-regulation of activated AR signaling via PKC stimulation. The aim of the present investigation was to identify the transcription factor that mediates melatonin's up-regulatory effect on p27(Kip1) in LNCaP and 22Rv1 prostate cancer cells. Deletion mapping and reporter assays of the p27(Kip1) promoter revealed that the putative melatonin-responsive transcription factor binds to a 116 base-pair region of the promoter sequence, which contains a potential nuclear factor kappa B (NF-κB) binding site. When the NF-κB binding site was abolished by site-directed mutagenesis, the stimulatory effect of melatonin on p27(Kip1) promoter activity was mitigated. Notably, melatonin inhibited the DNA binding of activated NF-κB via MT(1) receptor-induced PKA and PKC stimulation. Furthermore, melatonin's up-regulatory effect on p27(Kip1) transcription and consequent cell antiproliferation were abrogated by NF-κB activator but mimicked by NF-κB inhibitor. The results indicate that inhibition of constitutively active NF-κB via melatonin MT(1) receptor-induced dual activation of (Gα(s) ) PKA and (Gα(q) ) PKC can de-repress the p27(Kip1) promoter leading to transcriptional up-regulation of p27(Kip1) . MT(1) receptor-mediated inhibition of activated NF-κB signaling provides a novel mechanism supporting the use of melatonin in prostate cancer chemoprevention and therapy.
... Finally, melatonin, which itself has obvious anti-cancer actions, could further elevate the oncostatic effects of the combined therapies. Within the last two decades, there has been a major emphasis on the ability of melatonin to inhibit especially breast (Blask et al. 1992Blask et al. , 2005 Coleman & Reiter 1992; Cos & Sanchez-Barcelo 1994; Stevens & Davis 1996; Leon-Blanco et al. 2003) and prostate cancer (Philo & Berkowitz 1988; Lupowitz & Zisapel 1999; Marelli et al. 2000; Sainz et al. 2005; Shiu et al. 2003; Shiu 2007), a trend that continues to the current time ( Jung-Hynes et al. 2010a Shiu et al. 2010). Many of these investigations have been elegant and have unequivocally established a role for melatonin as an effective experimental oncostatic agent. ...
... Many of these investigations have been elegant and have unequivocally established a role for melatonin as an effective experimental oncostatic agent. What is perplexing , however, is the very wide range of mechanisms proposed to explain the processes by which melatonin suppresses the growth of breast and prostate cancer cells (Cos & Sanchez-Barcelo 1994; Yuan et al. 2002; LeonBlanco et al. 2003; Blask et al. 2005; Sainz et al. 2005; Jung-Hynes et al. 2010a Shiu 2007; Shiu et al. 2010; Proietti et al. 2011). How these multiple potential mechanisms by which melatonin modulates tumor cell proliferation will be reconciled awaits further investigations. ...
Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications.
... Clearly, the new evidence strengthens the mechanistic basis of the experimental support for the proposed rational use of MLT in translational clinical trials investigating the effectiveness of the pineal hormone in prostate cancer primary and secondary chemoprevention [44]. It is noteworthy that the demonstration of MT 1 receptor expression in the human prostate epithelium and verification of the MT 1 /PKA+PKC/p27 Kip1 signaling pathway in benign a Total RNA was extracted from RWPE-1 and 22Rv1 cells treated with or without 10 )9 , 10 )8 and 10 )7 M melatonin (MLT) or vehicle for 24 hr, and was reversely transcribed into cDNA. ...
... While the attenuation of the growth-promoting actions of androgen on the prostate gland by MLT via a PKCdependent mechanism has been recognized [24,44,45], the more direct antiproliferative action of MLT as a prostate growth suppressor has received less attention and consideration. Collectively, our previous and present results suggested that MLT can act not only as a negative modulator of the growth-promoting actions of androgen on the prostate gland, but also as a negative mitogenic hormonal regulator, exerting homeostatic control on human prostate epithelial cell growth via MT 1 /PKA+PKC/p27 Kip1 pathway, in functional antagonism to androgen, the dominant positive mitogenic endocrine regulator. ...
Circannual variation in the human serum levels of prostate-specific antigen, a growth marker of the prostate gland, has been reported recently. The present study was conducted to investigate the role of the photoperiodic hormone melatonin (MLT) and its membrane receptors in the modulation of human prostate growth. Expression of MT(1) and MT(2) receptors was detected in benign human prostatic epithelial tissues and RWPE-1 cells. MLT and 2-iodomelatonin inhibited RWPE-1 cell proliferation and up-regulated p27(Kip1) gene and protein expression in the cells. The effects of MLT were blocked by the nonselective MT(1)/MT(2) receptor antagonist luzindole, but were not affected by the selective MT(2) receptor antagonist 4-phenyl-2-propionamidotetraline. Of note, the antiproliferative action of MLT on benign prostate epithelial RWPE-1 cells was effected via increased p27(Kip1) gene transcription through MT(1) receptor-mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel, a signaling process which has previously been demonstrated in 22Rv1 prostate cancer cells. Taken together, the demonstration of the MT(1)/PKA+PKC/p27(Kip1) antiproliferative pathway in benign and malignant prostate epithelial cell lines indicated the potential importance of this MLT receptor-mediated signaling mechanism in growth regulation of the human prostate gland in health and disease. Collectively, our data support the hypothesis that MLT may function as a negative mitogenic hormonal regulator of human prostate epithelial cell growth.
... Certainly, that melatonin is an endogenously produced oncostatic agent has a large amount of experimental support. [40][41][42][43] Moreover, there are a remarkably large number of either proposed and/or documented mechanisms to explain how melatonin achieves its cancer inhibitory effects (Figure 1). These mechanisms range widely from membrane receptormediated actions of melatonin on growth factor uptake 44,45 to epigenetic modulation of cancer growth. ...
... These mechanisms range widely from membrane receptormediated actions of melatonin on growth factor uptake 44,45 to epigenetic modulation of cancer growth. 46 There is vast literature substantiating the ability of melatonin to not only limit the growth of already established tumors 40,42,43,[48][49][50] but also to prevent free radical-mediated damage to nuclear DNA; 51,52 thus, melatonin not only forestalls the promotion and progression of tumor growth but also may prevent tumor initiation by limiting the initial event, that is, DNA damage, that precedes the mutation necessary for tumor development. These data are supported by the general observations that aging is associated with a gradual decline in endogenous melatonin production, 53,54 whereas the incidence of cancer increases. ...
In industrialized countries, certain types of cancer, most notably, breast and prostate, are more frequent than in poorly developed nations. This high cancer frequency is not explained by any of the conventional causes. Within the past decade, numerous reports have appeared that link light at night with an elevated cancer risk. The three major consequences of light at night are sleep deprivation, chronodisruption, and melatonin suppression. Each of these individually or in combination may contribute to the reported rise in certain types of cancer. In this article, the potential mechanisms underlying the basis of the elevated cancer risk are briefly discussed. Finally, if cancer is a consequence of excessive nighttime light, it is likely that other diseases/conditions may also be exaggerated by the widespread use of light after darkness onset.
... The functional repertoire of melatonin, however, extends well beyond its control of annual cycles of sexual physiology in photoperiodic animals. The circadian rhythm of melatonin has been unequivocally linked to biological rhythmicity (Arendt, 2005;Masson-Pevet, 2007), sleep (Gorfine and Zisapel, 2009;Jan et al., 2009), immune function (Cardinali et al., 2008;Maldonado et al., 2009), blood pressure (Simko and Paulis, 2007;Reiter and Korkmaz, 2008), diabetes (Peschke, 2008;Korkmaz et al., 2008), neurodegenerative diseases (Pappolla et al., 2000;Reiter et al., 2004), ischemia/ reperfusion injury (Reiter et al., 2005a;Tengattini et al., 2008), cell physiology (Benitez-King, 2006), and cancer inhibition (Blask et al., 2005;Shiu, 2007;Korkmaz et al., 2009a), among others. Lerner and colleagues (1958) would surely be pleased to learn that the role of melatonin in skin physiology is also coming into focus (Slominski et al., 2007;Fischer et al., 2008). ...
... stimulation of antioxidative enzymes (Rodriguez et al., 2004;Tomas-Zapico and Coto-Montes, 2005) and inhibition of pro-oxidative enzymes (Pozo et al., 1994(Pozo et al., , 1997Hardeland, 2008), remains to be determined. It cannot be denied, however, that melatonin markedly reduces excessive oxidative damage under many experimental and clinical conditions where the molecular destruction occurs as a consequence of a high free radical-related disease or to aging (Poeggeler, 2005;Shiu, 2007;Reiter et al., 2008c). Whether this protection is physiological, or can only be achieved with pharmacological doses of the indoleamine, continues to be debated. ...
The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.
... 95 Although prion protein (PrPc) was once thought to be involved only in prion disease, new results show that PrPc may function in the biology of kidney cancer, prostate cancer, gastric cancer, and breast cancer. 96 Melatonin regulates the PrPC in CKD-mMSCs and enhances mitochondrial activity, thereby inhibiting CKD-mMSCs senescence. Melatonin in combination with diterpenoid kahweol induced up-regulation of p-53 upregulated modulator of apoptosis via C/EBP homologous protein induction and p-53 independent apoptosis pathway. ...
Melatonin, is a serotonin derived pineal gland hormone which has myriad of biological functions like regulating sleep- wake cycle, circadian rhythm, menstrual cycle, ageing, immunity and anti-oxidant. Melatonin synthesis and release is more pronounced during night whereas exposure to light decreases it. Evidences are mounting in the favor of therapeutic effects of melatonin in cancer prevention, treatment and delayed onset in various cancer subtypes. Melatonin exerts its anticancer effect through modification of its receptors such as MT1, MT2 and inhibition of cancer cell proliferation, epigenetic alterations (DNA methylation/ demethylation, histone acetylation/deacetylation), metastasis, angiogenesis, altered cellular energetics and immune evasion. Melatonin perform a significant function in immune-modulation, enhances innate and cellular immunity. Melatonin has remarkable impact on epigenetic modulation of gene expression and alters the transcription of genes. As adjuvant to cancer therapies, it acts by decreasing the side effects and also by boosting the therapeutic effects of chemotherapy. Since current treatments produce drug-induced unwanted toxicities and side effects, requires alternate treatments. Current review article is an attempt to summarize the mechanistic perspective of melatonin in different cancer subtypes like skin cancer, breast cancer, hepatic cancer, renal cell cancer, NSCLC, colon cancer, oral, neck, and head cancer. The various studies described in this review will give a firm basis for the future evolution of anticancer drugs.
... However, the agents currently used for cancer treatment are usually cytotoxic and have serious side effects that can reduce the quality of life of cancer patients [26]. Many epidemiological studies have shown that dietary habits, including antioxidant consumption, significantly decreased PC and CRC development [27][28][29]. ...
... Within the last few decades, melatonin has increasingly emerged in clinical oncology as a bioactive molecule with substantial anticancer properties and a pharmacological profile. Despite the substantial body of evidence linking chrono disruption and melatonin suppression to a higher prevalence of cancer, some experimental data showed that melatonin onset may act as an endogenously produced oncostatic agent [94][95][96][97][98][99]. A variety of mechanisms have been described by which a reduction of pineal or mitochondrial melatonin, levels may stimulate tumor growth [97,[100][101][102][103]. ...
The last four decades, we assist to an increasing scientific interest on melatonin, a circadian hormone, a metabolic regulator which influences not only plants’ metabolism and their defense against pathogens but mostly the animals and humans’ metabolic pathways, their response to circadian disruption, stress and burnout syndrome. In humans, as a hormonal regulator, produced in the pineal grand as well in mitochondria, melatonin is involved in different, complex intracellular signaling pathways, with antioxidant and immune stimulating effects, proving to act as a circadian synchronizer, as a preventive and therapeutic agent in many degenerative diseases, and especially in hormone-dependent cancers. Preclinical or clinical studies showed recently the mechanisms involved in regulating the cellular activity, its role in aging and circadian disturbances and impact on degenerative diseases. Melatonin proved to have an anti-inflammatory, antiapoptotic and powerful antioxidant effect by subtle mechanisms in mitochondrial metabolic pathways. This overview includes recent and relevant literature data related to the impact of endogenous and exogeneous melatonin on the prevention of cancer progression and treatment of various degenerative diseases. Metabolomics, an emerging new omics’ technology, based on high performance liquid chromatography coupled with mass spectrometry is presented as an encouraging technique to fingerprint and realize a precise evaluation and monitoring of the turnover of melatonin and its metabolites in different pathological circumstances.
... Abnormal levels of MEL in cancer patients indicate its participation in oncogenesis [3,4]. Significant antitumor effects of MEL upon different types of tumor cells have been reported [5]. ...
... 66,67 The oncostatic action of MLT is largely mediated by the MT1 receptor in melanoma, hepatoma and breast cancer cells, whereas the anti-oxidant action of MLT plays a more important role in glioma antiproliferation. 68 In conclusion, MLT suppressed the growth and proliferation of solid Ehrlich carcinoma by inducing apoptosis and by inhibiting tumour vascularization. Apart from improving the well-being of patients, the current data recommend MLT as a natural chemotherapeutic adjuvant to overcome cancer progression that deserves to be tested in a clinical trial. ...
The current work estimated the antitumour efficacy of melatonin (MLT) on the growth of Ehrlich ascites carcinoma cells inoculated intramuscularly into the hind limbs of female BALB/c mice and to compare its effects with those of adriamycin (ADR). After solid tumours developed, the animals were divided into the three following groups: the tumour bearing control, MLT‐treated (20 mg/kg body weight) and ADR‐treated (10 mg/kg body weight) groups. The results showed a significant reduction in the tumour masses of the treated animals in comparison with those of the control group. There were a significant decrease in the malondialdeyde level and a significant elevation of the glutathione concentration and the superoxide dismutase and catalase activities in the MLT and ADR groups. The current study indicated the increased expression levels of P53, caspase‐3 and caspase‐9 and the decreased expression levels of the rRNA and Bcl2. The MLT and ADR treatments resulted in histological changes, such as a marked degenerative area, the necrosis of neoplastic cells, the appearance of different forms of apoptotic cells and giant cells with condensed chromatin, and a deeply eosinophilic cytoplasm. The MLT and ADR treatments also significantly decreased the Ki‐67 protein and vascular endothelial growth factor (VEGF) expression levels in the tumour masses. In conclusion, similar to ADR‐treated tumour bearing mice, MLT suppressed the growth and proliferation of tumour by inducing apoptosis and by inhibiting tumour vascularization. The current data recommend MLT as a safe natural chemotherapeutic adjuvant to overcome cancer progression after a clinical trial validates these results.
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... 66,67 The oncostatic action of MLT is largely mediated by the MT1 receptor in melanoma, hepatoma and breast cancer cells, whereas the anti-oxidant action of MLT plays a more important role in glioma antiproliferation. 68 In conclusion, MLT suppressed the growth and proliferation of solid Ehrlich carcinoma by inducing apoptosis and by inhibiting tumour vascularization. Apart from improving the well-being of patients, the current data recommend MLT as a natural chemotherapeutic adjuvant to overcome cancer progression that deserves to be tested in a clinical trial. ...
The current work estimated the antitumour efficacy of melatonin (MLT) on the growth of Ehrlich ascites carcinoma cells inoculated intramuscularly into the hind limbs of female BALB/c mice and to compare its effects with those of adriamycin (ADR). After solid tumours developed, the animals were divided into the three following groups: the tumour bearing control, MLT-treated (20 mg/kg body weight) and ADR-treated (10 mg/kg body weight) groups. The results showed a significant reduction in the tumour masses of the treated animals in comparison with those of the control group. There were a significant decrease in the malondialdeyde level and a significant elevation of the glutathione concentration and the superoxide dismutase and catalase activities in the MLT and ADR groups. The current study indicated the increased expression levels of P53, caspase-3 and caspase-9 and the decreased expression levels of the rRNA and Bcl2. The MLT and ADR treatments resulted in histological changes, such as a marked degenerative area, the necrosis of neoplastic cells, the appearance of different forms of apoptotic cells and giant cells with condensed chromatin, and a deeply eosinophilic cytoplasm. The MLT and ADR treatments also significantly decreased the Ki-67 protein and vascular endothelial growth factor (VEGF) expression levels in the tumour masses. In conclusion, similar to ADR-treated tumour bearing mice, MLT suppressed the growth and proliferation of tumour by inducing apoptosis and by inhibiting tumour vascularization. The current data recommend MLT as a safe natural chemotherapeutic adjuvant to overcome cancer progression after a clinical trial validates these results
... It has been reported that MEL produces an anticancer effect in different types of tumor cells [3,4]. The abnormal levels of MEL in cancer patients indicate its significant role in oncogenesis [5]. ...
Melatonin is produced by the pineal gland. It can be regarded as an anticancer agent and used for combined therapy, owing to its oncostatic, antioxidant, and immunoregulatory activities. Retinoic acid is widely used for the treatment of acute promyelocytic leukemia; however, it has adverse effects on the human organism. We investigated the effect of melatonin and reduced concentrations of retinoic acid on the activation of proliferation in acute promyelocytic leukemiaon a cell model HL-60. The combined effect of these compounds leads to a reduction in the number of cells by 70% and the index of mitotic activity by 64%. Combined treatment with melatonin and retinoic acid decreased the expression of the Bcl-2. The mitochondrial isoform VDAC1 can be a target in the treatment of different tumors. The combined effect of and retinoic acid at a low concentration (10 nM) decreased VDAC1 expression. Melatonin in combination with retinoic acid produced a similar effect on the expression of the translocator protein. The coprecipitation of VDAC with 2′,3′-cyclonucleotide-3′-phosphodiesterase implies a possible role of its in cancer development. The combined effect of retinoic acid and melatonin decreased the activity of the electron transport chain complexes. The changes in the activation of proliferation in HL-60 cells, the mitotic index, and Bcl-2 expression under combined effect of retinoic acid (10 nM) with melatonin (1 mM) are similar to changes that are induced by 1 μM retinoic acid. Our results suggest that MEL is able to improve the action the other chemotherapeutic agent.
... These findings indicate a central role of melatonin in repressing prostate cancer progression, and further suggest the promise of melatonin as an anticancer agent. The therapeutic potential of this pineal secretory product is attributed to its diverse physiological functions that restrain the aggressive behaviors of prostate cancer cells [278]. ...
There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.
... 44 Studies showed that melatonin suppress proliferation of cancer cell line and induces apoptosis tumor cell and also it is promising for the treatment of prostat cancer, and breast cancers. 25,[45][46][47][48][49][50][51][52][53] A study has also emitted that melatonin can be effective on malaria. 54 ...
The concept of melatonin has become more important recently both in plants and in human who utilize plants for nutritional and health purposes. Melatonin, synthesized from L-tryptophan by enzyms, protects plants against difficult conditions. People have consumed these plants for their antioxidant, immunomodulator, antiinflammatory and anticancer effects. In parts of edible and non-edible plants, levels of melatonin are determined by cyclodextrin-modified micellar electrokinetic chromatography, enzyme-linked immuno sorbent assay, radioimmunoassay, high-performance liquid chromatography, liquid chromatography with electrochemical detection, liquid chromatography with fluorimetric detection, liquid chromatography-mass spectrometry, and liquid chromatography-ultraviolet spectrophotometry. In this review, biosynthesis of melatonin in both animal and plants, function of melatonin in plant kingdom, especially in medicinal/edible and nonedible plants, and detection of phytomelatonin content in those plants are presented.
... ure of melato Figure 2). In via the kidne 6-hydroxyme conjugated w 9,40]. Melato transformed ydroxymelato d by differen provokes th melatonin ca ough the ac ) and in the n by the act eradisperoxid obin or cytoc d indolic path incorporated in the blood stream; it also crosses the blood-brain barrier and the placenta, while at subcellular level, it is mainly incorporated in the nucleus and mitochondria. ...
... Experimental evidence is compelling that melatonin is an endogenously-produced oncostatic agent [57][58][59][60][61] and as a consequence, its frequent suppression at night as a result of any means including excessive illumination, may increase the possibility of cancer initiation and/or exaggerate the rate of growth of established tumors in humans. A variety of mechanisms have been described by which a reduction in melatonin levels may stimulate tumor growth [62][63][64][65][66][67][68][69][70]. ...
In the past two decades, the results of a number of epidemiological studies have uncovered an association between excessive light exposure at night and the prevalence of cancer. Whereas the evidence supporting this link is strongest between nighttime light and female breast and male prostate cancer, the frequency of other tumor types may also be elevated. Individuals who have the highest reported increase in cancer are chronic night shift workers and flight attendants who routinely fly across numerous time zones. There are at least two obvious physiological consequences of nighttime light exposure, i.e., a reduction in circulating melatonin levels and disruption of the circadian system (chronodisruption). Both these perturbations in experimental animals aggravate tumor growth. Melatonin has a long investigative history in terms of its ability to stymie the growth of many tumor types. Likewise, in the last decade chronodisruption has been unequivocally linked to a variety of abnormal metabolic conditions including excessive tumor growth. This brief review summarizes the processes by which light after darkness onset impedes melatonin production and disturbs circadian rhythms. The survey also reviews the evidence associating the ostensible danger of excessive nighttime light pollution to cancer risk. If an elevated tumor frequency is definitively proven to be a consequence of light at night and/or chronodisruption, it seems likely that cancer will not be the exclusive pathophysiological change associated with the rampant light pollution characteristic of modern societies. [J Exp Integr Med 2011; 1(1): 13-22]
... Additionally, melatonin has antitumor activity against several types of cancers including androgen-dependent prostate tumors [3], most probably through the MT1 receptor [4]. Several mechanisms have been proposed to explain the effects of melatonin in prostate cancer, including stimulation of apoptosis either by activation of c-JUN N-terminal kinase (JNK) and p-38 [5] and cell cycle inhibition by down-regulation of the transcriptional activity by androgens binding to their cognate receptors [6]. Another candidate mechanism underlying the antitumor effect of melatonin involves hypoxia signaling and the hypoxia-inducible factor-1α (HIF-1α). ...
Melatonin is known to exert antitumor activity in several types of human cancers, but the underlying mechanisms as well as the efficacy of different doses of melatonin are not well defined. Here, we test the hypothesis whether melatonin in the nanomolar range is effective in exerting antitumor activity in vivo, and examine the correlation with the hypoxia signaling mechanism, which may be a major molecular mechanism by which melatonin antagonizes cancer. To test this hypothesis, LNCaP human prostate cancer cells were xenografted into seven-week old Foxn1nu/nu male mice that were treated with melatonin (18 i.p. injections of 1 mg/kg in 41 days). Saline-treated mice served as control. We found that the melatonin levels in plasma and xenografted tissue were 4x and 60x higher, respectively, than in control samples. Melatonin tended to restore the redox imbalance by increasing expression of Nrf2. As part of the phenotypic response to these perturbations, xenograft microvessel density was less in melatonin-treated animals, indicative of lower angiogenesis, and the xenograft growth rate was slower (P<0.0001). These changes were accompanied by a reduced expression of Ki67, elevated expression of HIF-1α and increased phosphorylation of Akt in melatonin than saline-treated mice. We conclude that the beneficial effect of melatonin in reducing cancer growth in vivo was evident at melatonin plasma levels as low as 4 nM, and was associated to decreased angiogenesis. Higher HIF-1α expression in xenograft tissue indicates that the antitumor effect cannot be due to a postulated anti-hypoxic effect, but may stem from lower angiogenesis potential.This article is protected by copyright. All rights reserved.
... As already mentioned, one exception to this general rule is experimental prostate cancers which are probably normally directly inhibited by melatonin [185,186]. This action of melatonin is considered outside the scope of the current review and the readership is directed to other sources of this information [187,188]. ...
Melatonin has a wide variety of beneficial actions at the level of the gonads and their adnexa. Some actions are mediated via its classic membrane melatonin receptors while others seem to be receptor-independent. This review summarizes many of the published reports which confirm that melatonin, which is produced in the ovary, aids in advancing follicular maturation and preserving the integrity of the ovum prior to and at the time of ovulation. Likewise, when ova are collected for in vitro fertilization-embryo transfer, treating them with melatonin improves implantation and pregnancy rates. Melatonin synthesis as well as its receptors have also been identified in the placenta. In this organ, melatonin seems to be of particular importance for the maintenance of the optimal turnover of cells in the villous trophoblast via its ability to regulate apoptosis. For male gametes, melatonin has also proven useful in protecting them from oxidative damage and preserving their viability. Incubation of ejaculated animal sperm improves their motility and prolongs their viability. For human sperm as well, melatonin is also a valuable agent for protecting them from free radical damage. In general, the direct actions of melatonin on the gonads and adnexa of mammals indicate it is an important agent for maintaining optimal reproductive physiology.
... It was recently discovered that NQO2 is a third cellular site (MT3) where melatonin binds [20][21][22]. Melatonin, a neurohormone secreted by the pineal gland during the night, has been demonstrated to be anti-carcinogenic in several studies [23][24][25]. As part of the present research, we also conducted a preliminary study to examine whether there is a link between estrogen metabolism, NQO2 and melatonin. ...
The physiological function of NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase) is to detoxify potentially reactive quinones by direct transfer of two electrons. A similar detoxification role has not been established for its homologue NRH:quinone oxidoreductase 2 (NQO2). Estrogen quinones, including estradiol(E2)-3,4-Q, generated by estrogen metabolism, are thought to be responsible for estrogen-initiated carcinogenesis. In this investigation, we have shown for the first time that NQO2 catalyzes the reduction of electrophilic estrogen quinones and thereby may act as a detoxification enzyme. ESI and MALDI mass spectrometric binding studies involving E2-3,4-Q with NQO2 clearly support the formation of an enzyme–substrate physical complex. The problem of spontaneous reduction of substrate by cofactor, benzyldihydronicotinamide riboside (BNAH), was successfully overcome by taking advantage of the ping-pong mechanism of NQO2 catalysis. The involvement of the enzyme in the reduction of E2-3,4-Q was further supported by addition of the inhibitor quercetin to the assay mixture. NQO2 is a newly discovered binding site (MT3) of melatonin. However, addition of melatonin to the assay mixture did not affect the catalytic activity of NQO2. Preliminary kinetic studies show that NQO2 is faster in reducing estrogen quinones than its homologue NQO1. Both UV and liquid chromatography–tandem mass spectrometry assays unequivocally corroborate the reduction of estrogen ortho-quinones by NQO2, indicating that it could be a novel target for prevention of breast cancer initiation.
... It is noteworthy that p27 Kip1 down-regulation is a critical step in the development and maintenance of the malignant proliferative prostatic epithelial cell phenotype [37,38]. Clearly, this receptor-mediated signaling pathway provides us with the mechanistic basis to develop melatonin or melatonin receptor analogs for the prevention and treatment of human prostate cancer [39]. To gain a better understanding of the signal transduction of melatonin in prostate epithelial cell antiproliferation, it is important for us to identify the specific G proteins responsible for the relay of melatoninÕs antiproliferative signal from membrane MTNR1A receptor to downstream activation of PKA and PKC in parallel. ...
Melatonin has been shown to inhibit the proliferation of malignant and transformed human prostate epithelial cells by transcriptional up-regulation of p27(Kip1) expression via MTNR1A receptor-mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel. Given that melatonin MTNR1A receptor is a G protein-coupled receptor, this study was conducted to identify the specific G proteins that mediate the antiproliferative action of melatonin on human prostate epithelial cells. In 22Rv1 and RWPE-1 cells, knockdown of either Gα(s) or Gα(q) , but not Gα(i2) expression by RNA interference, abrogated the effects of melatonin on p27(Kip1) and cell proliferation. Conversely, cellular overexpression of activated mutants of Gα(s) and Gα(q) in 22Rv1 and RWPE-1 cells mimicked the effects of melatonin on prostate epithelial cell antiproliferation by increasing p27(Kip1) expression through downstream activation of PKA and PKC in parallel. Moreover, melatonin or 2-iodomelatonin induced elevation of adenosine-3',5'-cyclic monophosphate (cAMP) in 22Rv1 and RWPE-1 cells. The effects of 2-iodomelatonin on cAMP were blocked by the nonselective MTNR1A/MTNR1B receptor antagonist luzindole but were not affected by the selective MTNR1B receptor antagonist 4-phenyl-2-propionamidotetraline (4-P-PDOT). Furthermore, knockdown of Gα(s) mitigated the stimulatory effects of 2-iodomelatonin on cAMP. Collectively, the data demonstrated, for the first time, functional coupling of MTNR1A receptor to Gα(s) in cancerous or transformed human cells expressing endogenous melatonin receptors. Our results also showed that dual activation of Gα(s) and Gα(q) proteins is involved in the signal transduction of MTNR1A receptor-mediated antiproliferative action of melatonin on human prostate epithelial cells.
... As mentioned above, the vast majority of studies that have tested melatonin as an oncostatic agent have been concerned with its ability to inhibit tumour progression (Blask et al., 2005a; Korkmaz et al., 2009a; Vijayalaxmi et al., 2002). In addition to suppressing the proliferative activity of tumour cells (Cos and Sanchez-Barcelo, 2000; Panzer and Viljoen, 1997; Shiu, 2007), melatonin often enhances apoptosis in many cancer cells (Sainz et al., 2003). Moreover, the indole possess anti-metastatic actions, likely due to its ability to enhance the production of cell surface adhesion molecules (Cos and Sanchez-Barcelo, 2000) and by preventing the breakdown of the intracellular matrix (Ortiz-Lopez et al., 2009). ...
Melatonin (N-acetyl-5-methoxytryptamine) has revealed itself as an ubiquitously distributed and functionally diverse molecule. The mechanisms that control its synthesis within the pineal gland have been well characterized and the retinal and biological clock processes that modulate the circadian production of melatonin in the pineal gland are rapidly being unravelled. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. While many of these actions are mediated by well-characterized, G-protein coupled melatonin receptors in cellular membranes, other actions of the indole seem to involve its interaction with orphan nuclear receptors and with molecules, for example calmodulin, in the cytosol. Additionally, by virtue of its ability to detoxify free radicals and related oxygen derivatives, melatonin influences the molecular physiology of cells via receptor-independent means. These uncommonly complex processes often make it difficult to determine specifically how melatonin functions to exert its obvious actions. What is apparent, however, is that the actions of melatonin contribute to improved cellular and organismal physiology. In view of this and its virtual absence of toxicity, melatonin may well find applications in both human and veterinary medicine.
... The photoperioddependent waxing and waning of reproductive capability was later found to result from the changing duration of elevated nocturnal melatonin levels in the circulation (Reiter, 1980;Carter & Goldman, 1983). Since then, many other biological functions of melatonin have been reported including the regulation of circadian entrainment, sleep promotion, immuno-enhancement, oncostasis, etc. (Reiter, 1991a;Carrillo-Vico et al., 2005;Shiu, 2007;Zisapel, 2007). ...
Melatonin is a molecule present in a multitude of taxa and may be ubiquitous in organisms. It has been found in bacteria, unicellular eukaryotes, macroalgae, fungi, plants and animals. A primary biological function of melatonin in primitive unicellular organisms is in antioxidant defence to protect against toxic free radical damage. During evolution, melatonin has been adopted by multicellular organisms to perform many other biological functions. These functions likely include the chemical expression of darkness in vertebrates, environmental tolerance in fungi and plants, sexual signaling in birds and fish, seasonal reproductive regulation in photoperiodic mammals, and immunomodulation and anti-inflammatory activity in all vertebrates tested. Moreover, its waning production during aging may indicate senescence in terms of a bio-clock in many organisms. Conversely, high melatonin levels can serve as a signal of vitality and health. The multiple biological functions of melatonin can partially be attributed to its unconventional metabolism which is comprised of multi-enzymatic, pseudo-enzymatic and non-enzymatic pathways. As a result, several bioactive metabolites of melatonin are formed during its metabolism and some of the presumed biological functions of melatonin reported to date may, in fact, be mediated by these metabolites. The changing biological roles of melatonin seem to have evolved from its primary function as an antioxidant.
... Additionally, its presence has been confirmed in many plants [1,2], Chinese herbs [3], and unicellular organisms [4,5]. Melatonin participates in diverse functions of the body including sleep and circadian rhythm regulation, immunoregulation and free radical scavenging, and may have anti-cancer actions6789. Melatonin also protects organisms against both bacterial and viral infections by a variety of mechanisms101112 and has been shown to be beneficial for reversing symptoms of septic shock [13]. ...
Malaria, which infects more than 300 million people annually, is a serious disease. Epidemiological surveys indicate that of those who are affected, malaria will claim the lives of more than one million individuals, mostly children. There is evidence that the synchronous maturation of Plasmodium falciparum, the parasite that causes a severe form of malaria in humans and Plasmodium chabaudi, responsible for rodent malaria, could be linked to circadian changes in melatonin concentration. In vitro melatonin stimulates the growth and development of P. falciparum through the activation of specific melatonin receptors coupled to phospholipase-C activation and the concomitant increase of intracellular Ca2+. The Ca2+ signaling pathway is important to stimulate parasite transition from the trophozoite to the schizont stage, the final stage of intraerythrocytic cycle, thus promoting the rise of parasitemia. Either pinealectomy or the administration of the melatonin receptor blocking agent luzindole desynchronizes the parasitic cell cycle. Therefore, the use of melatonin antagonists could be a novel therapeutic approach for controlling the disease. On the other hand, the complexity of melatonin's action in malaria is underscored by the demonstration that treatment with high doses of melatonin is actually beneficial for inhibiting apoptosis and liver damage resulting from the oxidative stress in malaria. The possibility that the coordinated administration of melatonin antagonists (to impair the melatonin signal that synchronizes P. falciparum) and of melatonin in doses high enough to decrease oxidative damage could be a novel approach in malaria treatment is discussed.
... Melatonin, a hormone secreted mainly by the pineal gland in humans, plays a central role in the circadian cycle and is also wellrecognized as a powerful antioxidant. It has been marketed as a general health supplement in the United States since 1993 (Lewis and Clouatre, 1999) and has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder, and sexual dysfunction (Waldhauser et al., 1993; Sewerynek, 2002; Shiu, 2007). However, it is melatonin's role as a free radical scavenger and general antioxidative protectant that researchers first recognized may be beneficial for several neurodegenerative disorders. ...
Nine neurodegenerative diseases are caused by polyglutamine (polyQ) tract amplification in different proteins. The cytotoxicity of each of these proteins is associated with a misfolding of the mutant protein, resulting in the subsequent alteration of cellular processes and interactions as well as the interrelated formation of insoluble aggregates and other conformationally toxic species. However, the diseases differ in their pathology and tissue specificity of action, which may be due to protein context/regions neighboring the polyQ stretch. For the purpose of the studies presented in ths work, the polyQ containing human androgen receptor (AR) that causes the disorder spinal and bulbar muscular atrophy (SBMA) was used to model polyQ toxicity. In previous investigations, two putative phosphorylation sites of the AR were identified, and it was demonstrated that mutation of these sites appeared to cause conformational change in the protein. Therefore, these N-terminal serine residues were exchanged to alanine in the wild type AR (ARQ22/ARQ22dm) or a receptor with an amplified polyQ stretch (ARQ77/ARQ77dm). These mutants were then used to characterize variance in types of aggregates and the associated toxic profiles due to the different protein conformations that arose from the serine mutations. Evaluating changes in aggregation and toxicity in cultured cells and in a Drosophila model of SBMA, it was found that the effects of the conformational changes differed depending on the length of the polyQ stretch. Mutations in the ARQ22 resulted in a marked increase in aggregation as well as decreased survival rates and altered locomotion behavior in Drosophila. These results were similar but not as severe as the ARQ77/SBMA model. In quite the opposite manner, mutations in the ARQ77 caused a decrease in aggregation and a lessened toxic effect in Drosophila. Moreover, it was found that inhibitor compounds used to ameliorate polyQ toxicity were not as efficient in inhibiting the varied toxicities exhibited by both the ARQ22dm and ARQ77dm. Therefore, two distinct amino acid sites that profoundly modulate polyQ toxicity in the AR have been identified. These results can be further utilized to understand the conformational changes in the AR that lead to aggregation as well as the types of aggregates that lead to toxicity. Neun neurodegenerative Krankheiten sind auf die Verlängerung einer Polyglutamin (PolyQ) Sequenz in unterschiedlichen Proteinen zurückzuführen. Die Zytotoxizität von jedem dieser Proteine ist mit einer Fehlfaltung des mutierten Proteins assoziiert. Dadurch kommt es zu Veränderungen in zellulären Prozessen und Interaktionen, sowie der damit verbundenen Bildung von unlöslichen Aggregaten und anderen toxisch wirkenden Spezies. Die Polyglutaminerkrankungen unterscheiden sich jedoch in ihrer Pathogenese und gewebespezifischen Wirkung, was auf den jeweiligen Proteinkontext bzw. PolyQ-angrenzenden Sequenzbereich zurückzuführen sein könnte. Für die Studien der hier vorliegenden Arbeit wurde der polyglutaminhaltige humane Androgenrezeptor (AR), Auslöser der spinalen und bulbären Muskelatrophie (SBMA), als Modell verwendet, um die Toxizität der PolyQ-Verlängerung zu analysieren. In früheren Experimenten wurden zwei mögliche Phosphorylierungsstellen im AR identifiziert, und die Mutation dieser Stellen schien eine Konformationsänderung im Protein hervorzurufen. Ausgehend von diesen Befunden wurden nun diese N-terminalen Serin-Reste im Wildtyp AR (ARQ22) sowie in einem Rezeptor mit einer verlängerten PolyQ Sequenz (ARQ77) gegen Alanin ausgetauscht (ARQ22dm bzw. ARQ77dm). Mit Hilfe dieser Mutanten wurde dann der Effekt der durch die Serinmutation erzeugten Konformationsänderung auf die jeweiligen Aggregatformen und die damit verbundenen Toxizitätsprofile charakterisiert. Die Untersuchungen der Aggregation und Toxizität in kultivierten Zellen und in einem SBMA Drosophila Modell ergaben, dass sich die Effekte der Konformationsänderungen in Abhängigkeit von der Länge der PolyQ Sequenz unterscheiden. Im ARQ22 verursachten die Mutationen eine deutliche Verstärkung der Aggregation, sowie eine verminderte Überlebensrate und ein verändertes Bewegungsverhalten in Drosophila. Diese Veränderungen ähnelten dem Phänotyp des ARQ77/SBMA Modells, waren jedoch etwas schwächer ausgeprägt. Im Gegensatz dazu führten die Mutationen im ARQ77 zu einer Herabsetzung und Abschwächung der Aggregatbildung und Toxizität. Darüber hinaus erwiesen sich Inhibitoren, die zur Milderung der PolyQ Toxizität eingesetzt werden, als nicht sehr effektiv in der Hemmung der durch den ARQ22dm und AR77dm verursachten Toxizität. Somit wurden in dieser Arbeit zwei Aminosäurestellen identifiziert, welche die PolyQ-Toxizität des AR in gravierender Weise modulieren. Diese Ergebnisse können zukünftig genutzt werden, um zu klären, welche konformationellen Veränderungen im AR zur Aggregation führen und welche Aggregatformen für dessen toxische Wirkung verantwortlich sind.
... Moreover, because the prostate stroma seems to be involved in the carcinogenic evolution and progression of prostate epithelial tumor cells, it might be suggested that resveratrol, by targeting QR2, functions as a chemopreventive agent against prostate cancer by its integrative action against prostate cancer cells [13,14] as well as through its growth and gene regulatory control of normal PrSCs. It is noteworthy that QR2 has recently been found to act as a low-affinity melatonin receptor, MT3 [35,36]; this raises the possibility that QR2 might contribute to the prostate cancer chemopreventive activities of melatonin [37][38][39]. We hypothesize that QR2, by binding to melatonin, facilitates and promotes the cytosolic sequestration of androgen receptor, thereby inhibiting cell proliferation and prostate-specific antigen expression. ...
Resveratrol is a dietary polyphenol espoused to have chemopreventive activity against a variety of human cancer types. We first reported that resveratrol significantly decreases the proliferation of both androgen-dependent and hormone-refractory prostate cancer cells. However, the effects of resveratrol in normal prostate epithelial and stromal cells, particularly with regard to its uptake, subcellular distribution and intracellular targets, have not been investigated. To advance the knowledge on accessibility and cellular disposition of resveratrol in prostate cells, [(3)H] resveratrol, fractionation of cell extracts into subcellular compartments, Western blot analysis, resveratrol affinity column chromatography and flow cytometry were used to study the uptake and intracellular distribution of resveratrol in normally cultured prostate stromal (PrSCs) and epithelial cells (PrECs). Pretreatment of both PrSCs and PrECs for 2 days with resveratrol modulated its uptake and selectively increased its distribution to the membrane and organelle compartments. Resveratrol affinity column chromatography studies showed differential expression of a previously identified resveratrol-targeting protein, quinone reductase 2 (QR2), in PrSCs and PrECs. Flow cytometric analysis comparing resveratrol-treated and untreated PrSCs showed a large decrease in G(1)-phase and a concomitant increase in S and G(2)/M-phases of the cell cycle. These results suggest that resveratrol suppresses PrSC proliferation by affecting cell cycle phase distribution, which may involve the participation by QR2.
... Melatonin, an indolamine synthesized in the pineal gland at nighttime from serotonin, plays an important role in a multitude of physiological functions1234 and may be involved in human disorders including autism [5], cancer [6], and diabetes [7]. Arylalkylamine N-acetyltransferase (AANAT or serotonin N-acetyltransferase) is the key enzyme in the biosynthesis of melatonin. ...
Small laboratory animals have provided significant information about melatonin regulation, yet most of these organisms are nocturnal and regulate melatonin synthesis by mechanisms that diverge from those of humans. For example, in all rodents examined, melatonin secretion occurs with a time lag of several hours after the onset of darkness; in addition, arylalkylamine N-acetyltransferase (AANAT), the key enzyme in melatonin synthesis, displays dynamic transcriptional activation specifically at night in all rodents studied to date. In ungulates and primates including humans, on the other hand, melatonin secretion occurs immediately during the early night and is controlled by circadian posttranscriptional regulation of AANAT. We hypothesize that the diurnal Octodon degus (an Hystricognath rodent) could serve as an improved experimental model for studies of human melatonin regulation. To test this, we monitored melatonin production in degus using pineal microdialysis and characterized the regulation of melatonin synthesis by analyzing degu Aanat. Degu pineal melatonin rises with little latency at night, as in ungulates and primates. In addition, degu Aanat mRNA expression displays no detectable diurnal variation, suggesting that, like ungulates and primates, melatonin in this species is regulated by a posttranscriptional mechanism. Compared with AANAT from all rodents examined to date, the predicted amino acid sequence of degu AANAT is phylogenetically more closely related to ungulate and primate AANAT. These data suggest that Octodon degus may provide an ideal model system for laboratory investigation of mechanisms of melatonin synthesis and secretion in diurnal mammals.
... Increases in both the effector caspase-3 activity and the 85-kDa fragment resulting from PARP proteolysis [37] indicated a significant induction of apoptosis by melatonin. Similar results, with induction of cell death by melatonin in cancer cells, has been described in melanoma, neuroblastoma, prostate cancer, breast cancer and colon cancer cells alone or in combination with other compounds [27,32,[38][39][40][41]. Although different models of hepatic damage induced by aging, malaria or ischemia-reperfusion indicate an antiapoptotic effect of melatonin in the liver [18,42,43], there is also some evidence of induction of apoptosis in tumour hepatocytes by this compound [31,32]. ...
Melatonin reduces proliferation in many different cancer cell lines. However, studies on the oncostatic effects of melatonin in the treatment of hepatocarcinoma are limited. In this study, we examined the effect of melatonin administration on HepG2 human hepatocarcinoma cells, analyzing cell cycle arrest, apoptosis and mitogen-activated protein kinase (MAPK) signalling pathways. Melatonin was dissolved in the cell culture media in 0.2% dimethyl sulfoxide and administered at different concentrations for 2, 4, 6, 8 and 10 days. Melatonin at concentrations 1000-10,000 microM caused a dose- and time-dependent reduction in cell number. Furthermore, melatonin treatment induced apoptosis with increased caspase-3 activity and poly(ADP-ribose) polymerase proteolysis. Proapoptotic effects of melatonin were related to cytosolic cytochrome c release, upregulation of Bax and induction of caspase-9 activity. Melatonin treatment also resulted in increased caspase-8 activity, although no significant change was observed in Fas-L expression. In addition, JNK 1,-2 and -3 and p38, members of the MAPK family, were upregulated by melatonin treatment. Growth inhibition by melatonin altered the percentage or cells in G0-G1 and G2/M phases indicating cell cycle arrest in the G2/M phase. The reduced cell proliferation and alterations of cell cycle were coincident with a significant increase in the expression of p53 and p21 proteins. These novel findings show that melatonin, by inducing cell death and cell cycle arrest, might be useful as adjuvant in hepatocarcinoma therapy.
Background
Both apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) inhibition and melatonin suppress prostate cancer (PCa) growth.
Objective
This study evaluated the therapeutic efficiency of self-assembled and prostate-specific membrane antigen (PSMA)-targeted nanocarrier loading ¹²⁵I radioactive particles and encapsulating siRNA targeting APE1 (siAPE1) and melatonin for PCa.
Methods
The linear polyarginine R12 polypeptide was prepared using Fmoc-Arg-Pbf-OH. The PSMA-targeted polymer was synthesized by conjugating azide-modified R12 peptide to PSMA monoclonal antibody (mAb). Before experiments, the PSMA-R12 nanocarrier was installed with melatonin and siAPE1, which were subsequently labeled by ¹²⁵I radioactive particles. In vitro biocompatibility and cytotoxicity of nanocomposites were examined in LNCaP cells and in vivo biodistribution and pharmacokinetics were determined using PCa tumor-bearing mice.
Results
PSMA-R12 nanocarrier was ~120 nm in size and was increased to ~150 nm by melatonin encapsulation. PSMA-R12 nanoparticles had efficient loading capacities of siAPE1, melatonin, and ¹²⁵I particles. The co-delivery of melatonin and siAPE1 by PSMA-R12-¹²⁵I showed synergistic effects on suppressing LNCaP cell proliferation and Bcl-2 expression and promoting cell apoptosis and caspase-3 expression. Pharmacokinetics analysis showed that Mel@PSMA-R12-¹²⁵I particles had high uptake activity in the liver, spleen, kidney, intestine, and tumor, and were accumulated in the tumor sites within the first 8 h p.i., but was rapidly cleared from all the tested organs at 24 h p.i. Administration of nanoparticles to PCa tumors in vivo showed that Mel@PSMA-R12-¹²⁵I/siAPE1 had high efficiency in suppressing PCa tumor growth.
Conclusion
The PSMA-targeted nanocarrier encapsulating siAPE1 and melatonin is a promising therapeutic strategy for PCa and can provide a theoretical basis for patent applications.
Cancer cells require metabolic adaptations to a new cellular context characterized by accelerated proliferation, growth, production of building blocks, and a harsh microenvironment. Reprogrammed lipid metabolism has been found to be a major contributor to carcinogenesis and tumor progression. Prostate cancer cells are no exception to this rule. While dysregulated metabolism in prostate cancer affects carbohydrates, lipids, and amino acids, dysregulated lipid metabolism overshadows the other components of the metabolic orchestra. Prostate cancer shows a predominantly lipogenic phenotype and represents the best example of how lipids play a role in carcinogenesis and malignant progression. All the enzymes related to de novo lipogenesis and fatty acid catabolism are overexpressed in prostate malignancies. Fatty acid synthase (FAS), a key enzyme in de novo lipogenesis in tumors, contributes to growth and survival advantages, rather than to the energy-storage pathway. No other tumor types show such a high proportion of increased FAS levels in surgical specimens, more than 95%, as do prostate cancers. This finding, added to the overexpression of many other enzymes connected to lipid metabolism, confirms the lipogenic nature of prostate cancer. The reasons why prostate cancer metabolism is so lipogenic are related to androgenic modulation of the lipogenic enzymes and the nature of normal prostate cells that produce an important amount of citrate required by the seminal fluid. We may say that normal prostate cells are highly “citrogenic.” Malignant cells “inherit” this citrate-centered behavior but with a different purpose: to use citrate to synthesize fatty acids and produce energy through the Krebs cycle. Fatty acids are utilized to generate energy through beta-oxidation thanks to the overexpressed enzymes of this pathway. These characteristics make prostate cancer highly dependent on lipid metabolism.
Along with playing an important role in circadian rhythm, melatonin is thought to play a significant role in preventing cells from damage, as well as in the inhibition of growth and in triggering of apoptosis in malignant cells. Its relationship with circadian rhythms, energetic homeostasis, diet, and metabolism, is fundamental to achieve a better comprehension of how melatonin has been considered a chemopreventive molecule, though very few papers dealt with this issue. In this article, we tried to review the most recent evidence regarding the protective as well as the antitumoral mechanisms of melatonin, as related to diet and metabolic balance. From different studies, it was evident that an intracellular antioxidant defense mechanism is activated by upregulating an antioxidant gene battery in the presence of high-dose melatonin in malignant cells. Like other broad-spectrum antioxidant molecules, melatonin plays a vital role in killing tumor cells, preventing metastasis, and simultaneously keeping normal cells protected from oxidative stress and other types of tissue damage.
Background:
Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved.
Methods:
An umbrella review of the evidence across systematic reviews and narrative reviews of endogenous and exogenous (supplementation) MLT was undertaken. The Oxman checklist for assessing the methodological quality of the included systematic reviews was utilised. The following databases were searched: MEDLINE, EMBASE, Web of Science, CENTRAL, PsycINFO and CINAHL. In addition, reference lists were screened. We included reviews of the effects of MLT on any type of health-related outcome measure.
Results:
Altogether, 195 reviews met the inclusion criteria. Most were of low methodological quality (mean -4.5, standard deviation 6.7). Of those, 164 did not pool the data and were synthesised narratively (qualitatively) whereas the remaining 31 used meta-analytic techniques and were synthesised quantitatively. Seven meta-analyses were significant with P values less than 0.001 under the random-effects model. These pertained to sleep latency, pre-operative anxiety, prevention of agitation and risk of breast cancer.
Conclusions:
There is an abundance of reviews evaluating the effects of exogenous and endogenous MLT on health. In general, MLT has been shown to be associated with a wide variety of health outcomes in clinically and methodologically heterogeneous populations. Many reviews stressed the need for more high-quality randomised clinical trials to reduce the existing uncertainties.
We studied the effect of isoquinoline carboxamide (PK11195) applied alone or in combination with melatonin on the differentiation of N1E-115 mouse neuroblastoma cells (clone C-1300). PK11195 is a synthetic ligand of the mitochondrial translocator protein (TSPO), which is one of the mitochondrial proteins that are responsible for the opening of the mitochondrial pore (mPTP); expression of this protein is enhanced in different types of cancer cells. PK11195 is considered as a potential anticancer drug. It has been shown that PK11195 at a nontoxic/subtoxic concentration induces the differentiation of the N1Е-115 mouse neuroblastoma cells and suppresses cell proliferation; the magnitude of this effect coincides with the effect induced by melatonin at a nontoxic concentration. The combination of PK11195 with melatonin did not intensify its effect as a differentiation inducer. Based on the results of Western blot analysis, it has been hypothesized that the differentiation of N1Е-115 neuroblastoma cells is associated with the expression of mitochondrial 2’,3’-cyclonucleotide-3’-phosphodiesterase but not with the expression of the mitochondrial translocator protein TSPO.
This chapter describes the current body of knowledge regarding the additive effects of fish oil and bio-active agents on the prevention and remediation of clinical disorders. It discusses the singular effect of fish oil consumption in relation to a specific illness, followed by the reported synergistic/additive effects of fish oil combined with bio-active agents. There is substantial evidence that fish oil possesses various physiological activity benefits in human health. The chapter discusses concomitant applications of fish oil with bio-active compounds for the remediation of a variety of clinical disorders. By combinative therapy, the well-documented beneficial health effect of fish oil can possibly be maximized in various approaches. Although this area of research is still in its early stages, it has been receiving increasing attention with the realization that combinative application of fish oil and bio-active compounds may provide vital outcomes and facilitate progress toward the design of beneficial clinical therapies for human health. Studies aimed at finding superior combinative effects of fish oil and bio-active compounds, along with their mechanisms of action, may eventually lead to reductions in the mortality and morbidity rates associated with human health disorders and complications that are of growing concern in modern society.
Melatonin, the popular hormone of the darkness, is primarily synthesized in the pineal gland, and acts classically through the G-protein coupled plasma membrane melatonin receptors MT1 and MT2, respectively. Although some of the receptor mediated functions of melatonin, especially those on the (central) circadian system, have been more or less clarified, the functional meaning of MT-receptors in various peripheral organs are still not sufficiently investigated yet. There is, however, accumulating evidence for oncostatic effects of melatonin with both, antioxidative and MT-receptor mediated mechanisms possibly playing a role. This review briefly summarizes the physiology of melatonin and MT-receptors, and discusses the expression and function of MT-receptors in human cancer cells and tissues.
Biological rhythms are considered in the rational use of therapeutic agents to optimize the treatment of several diseases. In cancer, several stages of cell cycle are regulated by the circadian clock. Clock genes play a vital role in cell proliferation and apoptosis. Therefore, mutation/abnormal function of circadian clock genes could result in tumor development. Circadian rhythmicity can be used as a marker rhythm for tumor progression, as rhythm impairment increases along with tumor malignancy. Administration of drugs at a particular circadian phase has achieved the best anti-tumor activity. Pharmacological doses of melatonin significantly increase antioxidant levels, thereby decreasing free radical formation. In some cancer cell types, melatonin is known to inhibit cancer cell growth under in vitro conditions. The protective effect of S-allylcysteine, diallyl disulphide and α-ketoglutarate on NDEA treated rats showed that alternations in the rhythmicities of lipid peroxidation (TBARS) and antioxidant levels (SOD, CAT, GSH and GPX) could be normalized.
Melatonin is an important natural oncostatic agent, and our previous studies have found its inhibitory action on tumor angiogenesis, but the mechanism remains unclear. It is well known that vascular endothelial growth factor (VEGF) plays key roles in tumor angiogenesis and has become an important target for antitumor therapy. Pancreatic cancer is a representative of the most highly vascularized and angiogenic solid tumors, which responds poorly to chemotherapy and radiation. Thus, seeking new treatment strategies targeting which have anti-angiogenic capability is urgent in clinical practice. In this study, a co-culture system between human umbilical vein endothelial cells (HUVECs) and pancreatic carcinoma cells (PANC-1) was used to investigate the direct effect of melatonin on the tumor angiogenesis and its possible action on VEGF expression. We found HUVECs exhibited an increased cell proliferation and cell migration when co-cultured with PANC-1 cells, but the process was prevented when melatonin added to the incubation medium. Melatonin at concentrations of 1 μm and 1 mm inhibited the cell proliferation and migration of HUVECs and also decreased both the VEGF protein secreted to the cultured medium and the protein produced by the PANC-1 cells. In addition, the VEGF mRNA expression was also down-regulated by melatonin. Taken together, our present study shows that melatonin at pharmacological concentrations inhibited the elevated cell proliferation and cell migration of HUVECs stimulated by co-culturing them with PANC-1 cells; this was associated with a suppression of VEGF expression in PANC-1 cells.
In this study, the effects of melatonin or beta-glucan treatments on tumor growth, pro-oxidant, and antioxidant status in tumor tissue were investigated in Dunning 3327 MatLyLu prostatic adenocarcinoma model. Prostate cancer (PCa) was induced by single intradermal injection of 2 x 10(4) MatLyLu cells into the right hind leg of Copenhagen rats. Melatonin (10 mg/kg/daily; IP) or beta-glucan (50 mg/kg/daily; orally) treatments applied alone and together continued for 39 days. Melatonin or beta-glucan treatments alone or together inhibited tumor growth and decreased malondialdehyde (MDA) levels in tumor tissues of Dunning rats. However, there were no significant differences in tumor volumes and MDA levels among treatment groups. Melatonin and melatonin + beta-glucan treatments elevated glutathione (GSH) levels and superoxide dismutase, glutathione peroxidase, and glutathione transferase activities in tumor tissues. However, beta-glucan treatment did not influence GSH levels and antioxidant enzyme activities in tumor tissue of Dunning rats. These results indicate that melatonin and beta-glucan treatments alone or together inhibit tumor progression and oxidative stress in tumor tissues of rats with Dunning PCa.
Recently, a novel melatonin MT(1) receptor-mediated antiproliferative signaling mechanism involving transcriptional up-regulation of p27(Kip1) due to paralleled stimulation of protein kinase A (PKA) and protein kinase C (PKC), as a result of respective dual activation of upstream Gα(s) and Gα(q) , has been reported in 22Rv1 and RWPE-1 human prostate epithelial cells. Here, we demonstrate that melatonin inhibits the proliferation of LNCaP and VCaP prostate cancer cells via activation of the same MT(1) receptor-mediated antiproliferative signaling pathway. Knockdown of the expression of wild-type androgen receptor (AR) and/or structural/functional AR variants in LNCaP, VCaP, 22Rv1, and RWPE-1 cells resulted in abrogation of melatonin receptor-mediated antiproliferation, indicating that the antiproliferative signaling pathway MT(1) /(Gα(s) ) PKA + (Gα(q) ) PKC/p27(Kip1) activated by melatonin in human prostate epithelial cells is AR dependent. Furthermore, melatonin was shown to decrease androgen/AR-mediated transactivation of the prostate-specific antigen promoter in the prostate epithelial cell lines. Together, our data indicate the presence of reciprocal functional interactions between MT(1) receptor and AR signaling in malignant and nontumorigenic prostate epithelial cells. Notably, the dual actions of the MT(1) receptor-mediated antiproliferative signaling, leading to down-regulation of activated AR signaling and up-regulation of p27(Kip1) , constitute the mechanistic basis for the potential use of melatonin in chemoprevention of prostate cancer, as well as in a novel therapeutic strategy, comprising a combination of melatonin repletion and androgen depletion, for the treatment of advanced or relapsed disease.
The aim of the study was to evaluate the efficacy of a treatment with myo-inositol plus folic acid plus melatonin compared with myo-inositol plus folic acid alone on oocyte quality in women underwent in vitro fertilization (IVF) cycles.
A prospective, clinical trial.
Starting on the day of GnRH administration, 65 women undergoing IVF cycles were randomized in two groups to receive myo-inositol plus folic acid plus melatonin (32 women, group A), and myo-inositol plus folic acid (33 women, group B), administered continuously. Primary endpoints were number of morphologically mature oocytes retrieved (MII oocytes), embryo quality, and pregnancy rate. Secondary endpoints were the total number of oocytes retrieved (immature and mature oocytes), fertilization rate per number of retrieved oocytes and embryo cleavage rate.
The mean number of oocytes retrieved did not differ between the two groups (7.88 +/- 1.76 vs 7.67 +/- 1.88; P=0.65). Whereas the group cotreated with melatonin reported a significantly greater mean number of mature oocytes (6.56 +/- 1.64 vs 5.76 +/- 1.56; P=0.047) and a lower mean number of immature oocytes (1.31 +/- 0.74 vs. 1.91 +/- 0.68; P=0.001). The mean number of embyos of top-quality (class 1 and 2) resulted higher in the group A (1.69 +/- 0.64 vs 1.24 +/- 0.75; P=0.01). Fertilization rate did not differ between the two groups. A total of 22 pregnancies were obtained (13 in group A and 9 in group B; P=0.26). Clinical pregnancy rate and implantation rate were in tendency higher in the group cotreated with melatonin, although the differences did not reach statistical significance. Biochemical pregnancy rate and abortion rate were similar in both groups.
melatonin ameliorates the activity of myo-inositol and folic acid by improving oocyte quality and pregnancy outcome in women with low oocyte quality history.
Epidemiological studies have clearly shown that whole-grain cereals can protect against obesity, diabetes, CVD and cancers. The specific effects of food structure (increased satiety, reduced transit time and glycaemic response), fibre (improved faecal bulking and satiety, viscosity and SCFA production, and/or reduced glycaemic response) and Mg (better glycaemic homeostasis through increased insulin secretion), together with the antioxidant and anti-carcinogenic properties of numerous bioactive compounds, especially those in the bran and germ (minerals, trace elements, vitamins, carotenoids, polyphenols and alkylresorcinols), are today well-recognised mechanisms in this protection. Recent findings, the exhaustive listing of bioactive compounds found in whole-grain wheat, their content in whole-grain, bran and germ fractions and their estimated bioavailability, have led to new hypotheses. The involvement of polyphenols in cell signalling and gene regulation, and of sulfur compounds, lignin and phytic acid should be considered in antioxidant protection. Whole-grain wheat is also a rich source of methyl donors and lipotropes (methionine, betaine, choline, inositol and folates) that may be involved in cardiovascular and/or hepatic protection, lipid metabolism and DNA methylation. Potential protective effects of bound phenolic acids within the colon, of the B-complex vitamins on the nervous system and mental health, of oligosaccharides as prebiotics, of compounds associated with skeleton health, and of other compounds such as alpha-linolenic acid, policosanol, melatonin, phytosterols and para-aminobenzoic acid also deserve to be studied in more depth. Finally, benefits of nutrigenomics to study complex physiological effects of the 'whole-grain package', and the most promising ways for improving the nutritional quality of cereal products are discussed.
Metastatic Neuroendocrine Tumor (NET) to the pineal gland is a unique manifestation previously unreported in the literature. We describe an unusual case of metastatic bronchial NET to the pineal gland in a 71-year-old male patient. His primary NET had been resected six years previously and there was no indication of the presence of disseminated metastatic disease at that time. Due to increased uptake by the pituitary gland on the post-operative 111Indium-pentetreotide scintigraphy (Octreoscan), an intra-sellar mass was diagnosed and excised using a transsphenoidal approach; histology revealed an unrelated non-functional pituitary macroadenoma. Four years later, a new mass appeared on MRI, involving the pineal gland, and was diagnosed on biopsy as a metastatic lesion from the original bronchial NET. Since this lesion was not accessible to surgery, it was treated successfully with radiosurgery. The case suggests that NETs should be considered in the differential diagnosis of pineal gland metastases and that radiosurgery may be an effective alternative in the treatment of these patients.
Light is, clearly, a key to life on Earth and light, equally clearly, determines biological rhythmicity in organisms. Light does the latter by setting internal or endogenous clocks which allow a multitude of species, including man, to adjust their lives to changing external or environmental conditions. Critical changes over time occur from day to night and throughout the year. In this paper, we sum up how visible light provides electromagnetic information about environmental "time" via the ocular interface of newly discovered photoreceptive cells to a master clock in our brain, viz the suprachiasmatic nuclei [SCN], and how the SCN translate this input, with melatonin as a key biologic intermediary, into endogenous or biological time. We summarize experimental and epidemiological evidence suggesting how chronodisruption, a relevant disturbance of the temporal organization or order of physiology, endocrinology, metabolism and behaviour, is probably detrimental for human beings. On the basis of our synthesis, and in line with suggestions by other researchers voiced decades ago, light must, functionally, be considered as a drug equivalent. In this vein, the very timing, quality (wavelength), quantity (dose) and side effects, including chronodisruption, of light exposures can be critically important for health and disease in man. As a promising means to foster public health, we advocate an appropriate balance of exposures to the key Zeitgeber light in terms of "light hygiene", implying strong and appropriate rather than weak and confusing temporal information. This focus on "light hygiene", and thus on the key Zeitgeber light, does not mean to ignore that there are multiple entrainment pathways for our circadian clocks. Indeed, when dealing with light, chronodisruption and a multitude of adverse health effects, we ultimately need to consider Zeitgeber cues, and their possible interplay, beyond light alone. Confusions of the temporal programmes in humans can also stem from physical and social activities, stress and facets of food intake. And yet, since light possesses a rather unique and exclusive Zeitgeber role and in view of its ubiquitous nature, a specific, preventative focus on "light hygiene", as a contribution to a general "Zeitgeber hygiene", is warranted.
Melatonin, the main secretory product of the pineal gland, has been shown to exert an oncostatic activity in cancer cells. Recently, several studies have shown that melatonin has antiangiogenic properties. However, the mechanism by which melatonin exerts antiangiogenenic effects is not understood. Hypoxia inducible factor (HIF)-1 is a transcription factor which mediates adaptive response to changes in tissue oxygenation. HIF-1 is a heterodimer formed by the association of a constitutively expressed HIF-1 beta subunit and a HIF-1 alpha subunit, the expression of which is highly regulated. In this study, pharmacologic concentrations of melatonin was found to inhibit expression of HIF-1 alpha protein under both normoxic and hypoxic conditions in DU145, PC-3, and LNCaP prostate cancer cells without affecting HIF-1 alpha mRNA levels. Consistent with the reduction in HIF-1 alpha protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of vascular endothelial growth factor. We found that the suppression of HIF-1 alpha expression by melatonin correlated with dephosphorylation of p70S6K and its direct target RPS6, a pathway known to regulate HIF-1 alpha expression at the translational level. Metabolic labeling assays indicated that melatonin inhibits de novo synthesis of HIF-1 alpha protein. Taken together, these results suggest that the pharmacologic concentration of melatonin inhibits HIF-1 alpha expression through the suppression of protein translation in prostate cancer cells.
To develop a minimally invasive preventive measure for early osteoarthritis, the effect of melatonin on cartilage matrix synthesis of articular chondrocytes was evaluated in vitro in a pellet culture system. The chondrogenic markers were assessed using histology, TaqMan polymerase chain reaction, and western blot. Our results show that melatonin treatment yielded chondrocyte-pellets with a higher expression of chondrogenic markers consisting of collagen II, Sox 9, and aggrecan at both the mRNA and protein levels. A hypertrophic marker, collagen X, remained low. Moreover, up-regulation of internal transforming growth factor beta1 (TGF-beta1) expression was observed in the melatonin-treated cells. Our data indicate, for the first time, that the administration of melatonin enhances cartilage matrix synthesis of articular chondrocytes in a serum-containing pellet culture system, likely through the TGF-beta signal pathway. Melatonin may prove to be a highly valuable addition to current therapeutic models for degenerative cartilage repair.
To investigate the molecular basis of PTEN-mediated tumor suppression, we introduced a null mutation into the mouse Pten gene by homologous recombination in embryonic stem (ES) cells. Pten−/− ES cells exhibited an increased growth rate and proliferated even in the absence of serum. ES cells lacking PTEN function
also displayed advanced entry into S phase. This accelerated G1/S transition was accompanied by down-regulation of p27KIP1, a major inhibitor for G1 cyclin-dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts resulted in elevated levels of phosphatidylinositol
3,4,5,-trisphosphate, a product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to dosage-dependent increases
in phosphorylation and activation of Akt/protein kinase B, a well-characterized target of the phosphatidylinositol 3 kinase
signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten−/− cell survival. Our studies suggest that PTEN regulates the phosphatidylinositol 3,4,5,-trisphosphate and Akt signaling pathway
and consequently modulates two critical cellular processes: cell cycle progression and cell survival.
A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone.
The genetic bases underlying prostate tumorigenesis are poorly understood. Inactivation of the tumor-suppressor gene PTEN and lack of p27KIP1 expression have been detected in most advanced prostate cancers1,
2. But mice deficient for Cdkn1b (encoding p27Kip1) do not develop prostate cancer3,
4,
5. PTEN activity leads to the induction of p27KIP1 expression, which in turn can negatively regulate the transition through the cell cycle6. Thus, the inactivation of p27KIP1 may be epistatic to PTEN in the control of the cell cycle. Here we show that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins. Cell proliferation, but not cell survival, is increased in Pten
+/-/Cdkn1b
-/- mice. Moreover, Pten
+/-/Cdkn1b
-/- mice develop prostate carcinoma at complete penetrance within three months from birth. These cancers recapitulate the natural history and pathological features of human prostate cancer. Our findings reveal the crucial relevance of the combined tumor-suppressive activity of Pten and p27Kip1 through the control of cell-cycle progression.
Since melatonin, the major hormone of the pineal gland, has been shown to inhibit the growth of mammary tumors in animal models of human breast cancer, we examined the hypothesis that this indoleamine has the potential to inhibit breast cancer growth by directly inhibiting cell proliferation as exemplified by the growth of the estrogen-responsive human breast cancer cell line MCF-7 in culture. Concentrations of melatonin (10-9 M; 10-11 M), corresponding to the physiological levels present in human blood during the evening hours, significantly inhibited (P < 0.001) cell proliferation by as much as 60% to 78% as measured by either DNA content or hemocytometer cell counts. Melatonin's inhibitory effect was reversible since the logarithmic growth of MCF-7 cells was restored after melatonin-containing medium was replaced with fresh medium lacking melatonin. Not only was the inhibitory effect of melatonin absent at either pharmacological (10-7 M; 10-5 M) or subphysiological (10-15 M; 10-13 M) concentrations, but melatonin also failed to inhibit the proliferation of either human foreskin fibroblasts or the estrogen receptor-positive human endometrial cancer cell line RL95-2. Both transmission and scanning electron microscopy revealed several morphological changes that correlated with melatonin's inhibition of cell growth. After just 4 days of exposure to melatonin, MCF-7 cells exhibited reduced numbers of surface microvilli, nuclear swelling, cytoplasmic and ribosomal shedding, disruption of mitochondrial cristae, vesiculation of the smooth endoplasmic reticulum, and an increase in the numbers of autophagic vacuoles. These results support the hypothesis that melatonin, at physiological concentrations, exerts a direct but reversible, antiproliferative effect on MCF-7 cell growth in culture. This antiproliferative effect is associated with striking changes in the ultrastructural features of these cells suggestive of a sublethal but reversible cellular injury.
In an international collaboration project we combined cancers of the male genital tract among Inuit identified from routine cancer registry systems in the Circumpolar region (Alaska, Canada and Greenland) and compared incidence rates with rates in Denmark, Connecticut (USA) and Canadian non-Inuit. We observed a low risk of prostate cancer (standardized incidence ratio (SIR) 0.2-0.3) and the incidence rate of 7.8 per 100 000 (world standard) is among the lowest in the world. Dietary and not diagnostic factors are likely explanations of this finding. Testicular cancer also occurred with low rates (SIR 0.3-0.7) although only significantly so when compared with Denmark and Connecticut (USA) which have some of the world's highest incidence rates of this cancer. Penile cancer occurred with relatively high risk (SIR 1.8-3.0) based on rates among non-Inuit. The incidence is, however, lower than anticipated considering the possibility for shared risk factors with cancer of the uterine cervix.
Melatonin, the chief hormone secreted by the pineal gland, has been previously shown to inhibit human breast cancer cell growth at the physiological concentration of 1 nM in vitro. In this study, using the estrogen receptor (ER)-positive human breast tumor cell line MCF-7, we have shown that 10 microM L-buthionine-[S,R]-sulfoximine (L-BSO), an inhibitor of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis), blocks the oncostatic action of 1 nM melatonin over a 5-day incubation, indicating that glutathione is required for melatonin action. The result was repeated with ZR75-1 cells, suggesting that the glutathione requirement is a general phenomenon among ER+ breast cancer cells. Addition of exogenous glutathione (1 microM) to L-BSO-treated groups restored the melatonin response in both cell lines. Further demonstration of the importance of glutathione was shown using the ER- breast tumor cell line HS578T, which is normally unresponsive to melatonin. Growth in this cell line was inhibited in the presence of 1 microM ethacrynic acid (an inhibitor of glutathione S-transferase) plus 1 nM melatonin, and this effect was blocked with 10 microM L-BSO. We also observed a steady decrease of intracellular glutathione in MCF-7 cells over a 5-day incubation, suggesting that these cells metabolize glutathione differently than do normal cells.
The chromosomal region 10q23-24 is frequently deleted in a number of tumour types, including prostate adenocarcinoma and glioma. A candidate tumour-suppressor gene at 10q23.3, designated PTENor MMAC1, with putative actin-binding and tyrosine phosphatase domains has recently been described. Mutations in PTEN have been identified in cell lines derived from gliomas, melanomas and prostate tumours and from a number of tumour specimens derived from glial, breast, endometrial and kidney tissue. Germline mutations in PTEN appear to be responsible for Cowden disease. We identified five PTEN mutations in 37 primary prostatic tumours analysed and found that 70% of tumours showed loss or alteration of at least one PTEN allele, supporting the evidence for PTEN involvement in prostate tumour progression. We raised antisera to a peptide from PTEN and showed that reactivity occurs in numerous small cytoplasmic organelles and that the protein is commonly expressed in a variety of cell types. Northern blot analysis revealed multiple RNA species; some arise as a result of alternative polyadenylation sites, but others may be due to alternative splicing.
Images
Figure 1
Figure 2
Figure 3
The growth of rat hepatoma 7288CTC in vivo is stimulated by the uptake of linoleic acid (LA) and its metabolism to 13-hydroxyoctadecadienoic acid (13-HODE), an important mitogenic signaling molecule within this tumor. Conversely, the growth of a variety of experimental cancers in vivo is inhibited by either physiological or pharmacological levels of the pineal gland hormone melatonin, although the mechanism(s) are unknown. We tested the hypothesis that the mechanism of melatonin's anticancer action in vivo involves the inhibition of tumor LA uptake and metabolism to 13-HODE in hepatoma 7288CTC. Tumor uptake of LA and release of 13-HODE, measured in tissue-isolated rat hepatoma 7288CTC at 4-h intervals over a 24-h period, were highest during the light phase and lowest during the mid-dark phase, when plasma melatonin levels were lowest and highest, respectively. Pinealectomy eliminated this rhythm of tumor LA uptake and 13-HODE production, indicating that it was driven by the circadian melatonin rhythm. Perfusion of tissue-isolated tumors in situ with melatonin (1 nM) rapidly and reversibly inhibited the uptake of plasma fatty acids (FAs), including LA, and its metabolism to 13-HODE. These inhibitory effects of melatonin on tumor FA uptake and 13-HODE release were completely reversed by perfusion of tumors in situ with melatonin receptor antagonist S-20928, pertussis toxin, forskolin, or 8-bromo-cAMP. Perfusion of tumors in situ with melatonin also decreased tumor [3H]thymidine incorporation and DNA content; these effects on DNA synthesis were also prevented by the coperfusion of tumors with melatonin and S-20928, pertussis toxin, forskolin, 8-Br-cAMP, or 13-HODE. Pinealectomy stimulated tumor growth, LA uptake and metabolism to 13-HODE, and FA storage in hepatoma 7288CTC, whereas melatonin administration (200 microg/day) was inhibitory in vivo. Northern blot analysis revealed that, compared with normal liver tissue, hepatoma 7288CTC overexpressed mRNA transcripts for a plasma membrane-associated FA transport protein (FATP). FATP mRNA expression was unaffected by the treatment of tumor-bearing rats with daily afternoon melatonin injections or exposure to constant light. These results support a novel mechanism of tumor growth inhibition by melatonin involving a melatonin receptor-mediated suppression of cAMP levels, resulting in diminished tumor FA transport, possibly via decreased FATP function. The inhibition of these signal transduction events by melatonin culminates in the suppression of LA uptake, LA metabolism to the mitogenic signaling molecule 13-HODE, and cancer growth.
Growth of hepatoma 7288CTC in male Buffalo rats is directly dependent on uptake of linoleic acid (LA) from the arterial blood. One to 5% of the LA taken up is converted to 13-hydroxyoctadecadienoic acid (HODE), an agent that enhances epidermal growth factor-dependent mitogenesis. The role of 13-HODE in LA-dependent growth of solid tumors is not known. In this study, we examined LA uptake and 13-HODE formation on growth of tissue-isolated hepatoma 7288CTC in vivo and on [3H]thymidine incorporation and DNA content during perfusion in situ. Fatty acid uptake and metabolite release were determined from arteriovenous difference measurements. Tumor-bearing and blood donor rats were fed either LA-sufficient or -deficient diets. Hepatoma 7288CTC removed LA from the arterial blood and released 13-HODE [and a small amount of 13-ketooctadecadienoic acid (KODE)] into the venous blood both in vivo and during perfusion. Treatment with the lipoxygenase inhibitor nordihydroguaiaretic acid (10 microM) did not affect tumor LA uptake, but inhibited release of 13-HODE and 13-KODE in vivo and during perfusion, suppressed growth in vivo, and inhibited [3H]thymidine incorporation during perfusion. The addition of 13-HODE to the nordihydroguaiaretic acid-containing whole blood perfusate increased the rate of [3H]thymidine incorporation 10 times and nearly doubled tumor DNA content; the addition of 13-KODE or 9-HODE had no effect. 13-HODE and 13-KODE were not released from tumors growing in rats fed a LA-deficient diet, and the rates of tumor growth in vivo and [3H]thymidine incorporation during perfusion were decreased. The addition of 13-HODE to the LA-deficient blood perfusate promoted tumor 13-HODE uptake and a dose-dependent increase in [3H]thymidine incorporation and tumor DNA content. These results provide strong evidence that 13-HODE is the mitogenic signal responsible for LA-dependent growth in hepatoma 7288CTC in vivo.
The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting
that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer
progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific
antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell
line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473
phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27Kip1 cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated
transcription of p27Kip1. To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed
in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically
reduced p27Kip1 expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence
and suggest that diminished p27Kip1expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.
The pineal hormone melatonin has been shown to exert a direct oncostatic activity on neoplastic cells, particularly from breast cancer. In the present study, we evaluated the effects of melatonin on the proliferation and on the cell cycle distribution of human androgen-independent DU 145 prostate cancer cells. Experiments were also performed to gain insights into the possible mechanism of action of the hormone.
The effects of melatonin on DU 145 cell proliferation was analyzed by counting the cells by hemocytometer at the end of treatment. The effects of the pineal hormone on cell cycle distribution were evaluated by FACS analysis. RT-PCR studies were performed to detect Mel(1a) and Mel(1b) expression in DU 145 cells. The cellular localization of (125)I-melatonin binding sites was investigated by radioreceptor assay. A commercially available binding-protein assay kit was utilized to evaluate intracellular cAMP levels.
Melatonin, in physiological doses, significantly inhibited DU 145 cell proliferation and induced cell cycle withdrawal by accumulating cells in G0/G1 phase. The mRNA for Mel(1a) receptors was found to be expressed in DU 145 cells; however, by radioreceptor assay, no binding sites for (125)I-melatonin could be detected in membrane preparations, suggesting that, in these cells, the level of translation of this mRNA is too low to possibly mediate the antiproliferative action of the hormone. In agreement with this hypothesis, melatonin did not affect forskolin-induced intracellular cAMP accumulation. Binding sites for (125)I-melatonin were found in nuclear extracts of DU 145 cells.
Melatonin exerts a direct oncostatic activity on human androgen-independent prostate cancer cells, by affecting cell cycle progression. This activity seems to be mediated by nuclear, but not by membrane, receptors.
p27Kip1 is a cyclin‐dependent kinase inhibitor whose down‐regulation has been observed in several tumour models, including breast, colorectal, and gastric carcinomas. The purpose of this study was to assess p27Kip1 protein expression in normal and benign prostatic epithelia as well as the possible existence of abnormalities in prostate carcinoma progression. p27Kip1 expression was immunohistochemically analysed in 51 normal tissue samples, 11 nodular hyperplasias (NH), 22 high‐grade prostatic intraepithelial neoplasias (PIN), 56 localized prostate adenocarcinomas, and 19 metastases. Immunoblotting was performed in ten cases. Normal prostate epithelium and NH showed diffuse and intense p27Kip1 nuclear expression in most cases. A significant p27Kip1 down‐regulation was observed in many carcinomas when compared with benign epithelium. Forty‐seven cases (84 per cent) were low p27Kip1 expressors (<50 per cent positive cells) and nine cases (16 per cent) were high p27Kip1 expressors. p27Kip1 down‐regulation was also consistently seen in PIN. Fourteen out of 19 metastases (74 per cent) were low p27Kip1 expressors. Six metastatic samples had their corresponding primary tumour analysed and three cases showed decreased expression in the metastasis. It is concluded that p27Kip1 is constitutively expressed in normal and benign prostatic tissue. This expression is clearly down‐regulated in neoplastic progression from the preinvasive lesions through invasive carcinoma and metastases and this therefore occurs in early stages of neoplastic transformation. Copyright © 1999 John Wiley & Sons, Ltd.
Prostate cancer is a complex, multifactorial disease with genetic and environmental factors involved in its etiology. The search for genetic determinants involved in the disease has proven to be challenging, in part because such complex diseases are often not amenable to characterization by linkage analysis and positional cloning as is the case for diseases with simple Mendelian genetic inheritance. Prostate cancer susceptibility loci that have been reported so far include HPC1 (1q24-q25), PCAP (1q42-q43), HPCX (Xq27-q28), CAPB (1p36), HPC20 (20q13), HPC2/ELAC2 (17p11) and 16q23. Prostate cancer aggressiveness loci have also been reported (5q31-q33, 7q32 and 19q12). Further complicating the process is the existence of polymorphisms in several genes associated with prostate cancer including, AR, PSA, SRD5A2, VDR and CYP isoforms. These polymorphisms, however, are not thought to be highly penetrant alleles in families at high risk for prostate cancer. It is clear that prostate cancer etiology involves several genetic loci with no major gene accounting for a large proportion of susceptibility to the disease.
Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG and ETV1, were identified as outliers in prostate cancer. We identified recurrent gene fusions of the 5 ¶ untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlier expression. By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1. Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. These results have implications in the development of carcinomas and the molecular diagnosis and treatment of prostate cancer.
Background
Potential involvement of the mt1 receptor in the antiproliferative action of melatonin on androgen-sensitive LNCaP cells, and melatonin-induced modulation of androgen-insensitive PC-3 cell growth, have been reported in vitro. The effects of melatonin on prostate cancer cell proliferation and their association with mt1 receptor expression were investigated in athymic nude mice xenograft models of LNCaP and PC-3 cells.Methods
Daily saline or melatonin (4 μg/g body weight) was given to nude mice before or after tumor cell inoculation. Tumor volume was measured periodically, and expression of PCNA, cyclin A, PSA, and mt1 receptor was assessed by immunohisto(cyto)chemistry and/or Western blotting.ResultsMelatonin inhibited the growth of LNCaP tumors, without affecting the growth of PC-3 xenografts, in nude mice. It induced significant decreases in the expression of PCNA, cyclin A, and PSA in LNCaP tumors. Expression of mt1 receptor protein was demonstrated in LNCaP cells, but not in PC-3 cells, both in vivo and in vitro.Conclusions
The antiproliferative action of melatonin on LNCaP tumor growth was demonstrated in vivo, and its association with mt1 receptor protein expression suggests the potential involvement of the receptor in the antitumor activity of the pineal gland hormone. Prostate 46:52–61, 2001. © 2001 Wiley-Liss, Inc.
The purpose of this study was to investigate the effects of time of year and demographic variables on the amplitude of melatonin production in normal human subjects. Melatonin production was estimated by measuring the overnight excretion of its major urinary metabolite, 6-hydroxymelatonin. Urine was collected on three consecutive nights in the summer from a sample of 60 normal subjects balanced for sex and age. The collections were repeated in a subgroup during the winter. Melatonin production clearly declined with age but was not influenced by other demographic variables or by season of the year.
The objective of the present study was to assess the toxicology of melatonin (10 mg), administered for 28 days to 40 volunteers randomly assigned to groups receiving either melatonin (N=30) or placebo (N=10) in a double-blind fashion. The following measurements were performed: polysomnography (PSG), laboratory examinations, including complete blood count, urinalysis, sodium, potassium and calcium levels, total protein levels, albumin, blood glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), urea, creatinine, uric acid, glutamic-oxalacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT), bilirubin, alkaline phosphatase, gama-glutamic transaminase (GGT), T3, T4, TSH, LH/FSH, cortisol, and melatonin serum concentrations. In addition, the Epworth Somnolence Scale (ESS) and a sleep diary (SD) were also applied to the volunteers 1 wk before each PSG. In addition, the volunteers were asked about possible side effects (SE) that appeared during the treatment. The study was carried out according to the following timetable: Visit 0, filling out the term of consent and inclusion criteria; Visit 1, PSG, laboratory examinations, ESS, SD, melatonin serum concentrations; Visit 2, SD, melatonin serum concentrations, SE; Visit 3, melatonin serum concentrations, PSG, ESS, SE; Visit 4, laboratory examinations, SE, melatonin serum concentrations, SD; and Visit 5, PSG, ESS, SE. Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group. No other differences between the placebo and melatonin groups were obtained. In the present study we did not observe, according to the parameters analyzed, any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study.
Melatonin, the hormone secreted by the pineal gland at night, has recently been found to attenuate growth and viability of benign human prostate epithelial cells. Estradiol suppressed these responses by effecting a protein kinase C mediated inactivation of melatonin receptors. In the present study, the effects of melatonin on growth and viability of the human androgen-sensitive prostatic tumor cell line-LNCaP and the influence of estradiol on these responses were explored.Melatonin inhibited 3H-thymidine incorporation into LNCaP cells at physiological concentrations. This response decayed within 24 h. The inactivation of the response slowed down in the presence of the protein kinase C inhibitor GF-109203X. Estradiol also inhibited 3H-thymidine incorporation and its effects were additive to those of melatonin. Suppression of DNA content was observed in cells treated for 2 days with melatonin (0.1 nM); this suppression was maintained for longer periods in the presence than in the absence of estradiol. In addition, estradiol and melatonin slightly and additively decreased cell viability.These results demonstrate for the first time a direct interaction of melatonin with androgen-sensitive prostate tumor cells leading to attenuation of cell growth. They also show that unlike in benign prostate epithelial cells, estrogen attenuates LNCaP cell growth and supports rather than inactivates melatonin's action.
Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality.
To perform a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials.
135,967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d).
PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and meta-analyses. No language restrictions were applied.
3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available.
9 of 11 trials testing high-dosage vitamin E (> or =400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons (95% CI, 3 to 74 per 10,000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was -16 per 10,000 persons (CI, -41 to 10 per 10,000 persons; P > 0.2). A dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d.
High-dosage (> or =400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult.
High-dosage (> or =400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.
The hypothesis that diminished function of the pineal gland may promote the development of breast cancer in human beings is suggested by the relation between breast cancer and prolonged oestrogen excess, and by the observation that the pineal secretion, melatonin, inhibits ovarian oestrogen production, pituitary gonadotrophin production, and sexual development and maturation. The hypothesis is supported by the following points. (1) Pineal calcification is commonest in countries with high rates of breast cancer and lowest in areas with a low incidence; the incidences of pineal calcification and of breast cancer are moderate among the black population in the United States. (2) Chlorpromazine raises serum-melatonin; there are reports that psychiatric patients taking chlorpromazine have a lower incidence of breast cancer. (3) Although information is lacking on breast cancer, the pineal and melatonin may influence tumour induction and growth in experimental animals. (4) The demonstration of a melatonin receptor in human ovary suggests a direct influence of this hormone on the ovarian function, and possibly oestrogen production. (5) Impaired pineal secretion is believed to be an important factor triggering puberty (early menarche is a risk factor for breast cancer).
The circadian rhythms of melatonin and 6-sulfatoxymelatonin (aMT6s) were analyzed in serum and urine of young men (YM, n = 8), of elderly patients with benign prostatic hyperplasia (BPH, n = 7) and of patients of similar age with primary prostate cancer (PC, n = 9). The data expressed as concentration and in urine also as hourly excreted quantity were analyzed chronobiologically by the single cosinor method and, subsequently submitted to linear regression analyses. Circadian rhythms were detected in all cases except for the excreted quantity of melatonin. The circadian patterns of melatonin and aMT6s in serum were very similar in the different groups and regression analyses showed close correlations between both variables. MESOR and amplitude were significantly depressed in PC (40-60%) as compared to BPH and YM indicating that the depression of serum melatonin in PC is due to a reduced pineal activity and is not caused by an enhanced metabolic degradation in the liver. Acrophases of serum melatonin occurred between 01:34 and 03:26 h and of serum aMT6s between 03:58 and 04:35 h. Circadian rhythms similar to those of serum melatonin and aMT6s were found in urine, particularly for aMT6s excretion as well as melatonin concentration; the determination of both parameters in overnight urine samples closely correlated with the nocturnal peak of circulating melatonin. These results imply that it is feasible to estimate changes in pineal function of prostate cancer patients by means of non-invasive determination using urinary melatonin and aMT6s.
The available data on potential alterations in serum melatonin (MLT) levels during a human lifetime are fragmentary and inconsistent. We, therefore, measured day- and nighttime serum MLT concentrations in 367 subjects (210 males and 157 females), aged 3 days to 90 yr. Blood samples were collected between 0730 and 1000 h and between 2300 and 0100 h. Serum MLT levels were measured by RIA. The mean nighttime serum MLT concentration was low during the first 6 months of life, i.e. 27.3 +/- 5.4 (+/- SE) pg/mL (0.12 +/- 0.02 nmol/L). It then increased to a peak value at 1-3 yr of age [329.5 +/- 42.0 pg/mL; (1.43 +/- 0.18 nmol/L)], and it was considerably lower [62.5 +/- 9.0 pg/mL; (0.27 +/- 0.04 nmol/L)] in individuals aged 15-20 yr. During the following decades serum MLT declined moderately until old age (70-90 yr of age), i.e. 29.2 +/- 6.1 pg/mL (0.13 +/- 0.03 nmol/L). This biphasic MLT decline follows 2 exponential functions with different slopes (from age 1-20 yr: r = -0.56; P less than 0.001; y = 278.7 X e -0.09x; from age 20-90 yr: r = -0.44; P less than 0.001; y = 84.8 X e -0.017x). The decrease in nocturnal serum MLT in children and adolescents (1-20 yr) correlated with the increase in body weight (r = -0.54; P less than 0.001) and body surface area (r = -0.71; P less than 0.001). At a later age (20-90 yr) there was no correlation among these variables. Daytime serum MLT levels were low and no age-related alterations were found. This study revealed major age-related alterations in nocturnal serum MLT levels. The negative correlation between serum MLT and body weight in childhood and adolescence is evidence that expansion of body size is responsible for the huge MLT decrease during that period. The moderate decline at older ages must derive from other factors.
Breast cancer is frequently a hormone-dependent tumour, and several studies have suggested that the pineal gland hormone melatonin may influence the growth and development of this malignancy. Subcutaneous injections of melatonin have been shown to inhibit, and pinealectomy to enhance, the development of dimethyl benz(a)anthracene (DMBA)-induced mammary tumours in rats. Use of the psychotropic drug thorazine, which increases plasma melatonin levels, has been associated with a decreased incidence of breast cancer in psychiatric patients. Calcification of the pineal gland has been correlated with an increased incidence of breast cancer in women. While the mechanism by which melatonin influences these tumours is unknown, both human breast cancer and DMBA-induced tumours contain oestrogen receptors (ER) and respond to changes in the oestrogen milieu. We therefore wondered whether melatonin might be altering ER binding activity of these tumours. We report here that in vitro incubation of MCF-7 human breast cancer cells with melatonin in physiological conditions increased the cytoplasmic and nuclear ER activity of these cells within 40 min, giving no change in the equilibrium dissociation constant (Kd) of the receptor. This induction was blocked by cycloheximide, and thus requires continuous protein synthesis. The modulation of ER binding activity of breast cancer by another endogenous hormone may be important for understanding the behaviour and treatment of this disease, and may provide insight into the factors regulating the synthesis and metabolism of steroid hormone receptors.
Plasma melatonin concentrations were determined over a period of 24 hours in 20 women with clinical stage I or II breast cancer. In ten of the patients, whose tumors were estrogen receptor positive, the nocturnal increase in plasma melatonin was much lower than that observed in eight control subjects. Women with the lowest peak concentration of melatonin had tumors with the highest concentrations of estrogen receptors. A significant correlation was found between the peak plasma melatonin concentration and the tumor estrogen receptor concentration in 19 of the patients. These data suggest that low nocturnal melatonin concentrations may indicate the presence of estrogen receptor positive breast cancer and could conceivably have etiologic significance.
Serum melatonin concentrations were determined by RIA in 81 healthy humans, aged 1-92 yr. The daytime (0900-1100) serum levels of melatonin decreased progressively with advancing age. No sex difference was noted. The nocturnal rise of serum melatonin in the aged group was significantly reduced compared with that in the young group. These results suggest that serum melatonin may be secreted under the age-related neural control of pineal metabolism.
The incidence of clinically detected prostate cancer is increasing with more frequent diagnosis in younger male patients. Whether this represents a genuine increase in incidence or earlier detection is not clear. To understand better the evolution and early changes of prostate cancer we evaluated 152 prostate glands from young male patients 10 to 49 years old. Of the prostates 98 were from African-Americans and 54 were from white patients. Prostatic intraepithelial neoplasia was identified in 0%, 9%, 20 and 44%, and small foci of histological cancer in 0%, 0%, 27% and 34% of the male patients in the second, third, fourth and fifth decades of age, respectively. The majority of the cases of prostatic intraepithelial neoplasia were of low grade. High grade prostatic intraepithelial neoplasia, found in 5 prostates, was first identified in the fifth decade. All 5 cases occurred in prostates containing histological carcinoma. Incidental carcinoma was detected with a similar frequency in white and black patients. The cancerous foci were of similar size with a tendency for cancer in black patients to be multifocal, particularly in those in the fifth decade. We conclude that prostatic intraepithelial neoplasia and histological cancers are surprisingly common in young male patients of both races. The evolution of prostatic intraepithelial neoplasia and focal histological cancers is not clear but it appears to present several decades earlier than clinically detected carcinoma. The natural history of prostate cancer must encompass many more years (decades) than has been previously realized. In addition, the initiating events leading to clinically relevant prostate cancers likely occur at a remarkably young age.
The paper briefly reviews the data which shows that the circadian production and secretion of melatonin by the pineal gland can impart both daily, i.e., clock, and seasonal, i.e., calendar, information to the organism. The paper summarizes the 3 patterns of nocturnal melatonin production that have been described. Clearly, regardless of the pattern of nocturnal melatonin production a particular species normally displays, the duration of nightime elevated melatonin is proportional to the duration of the night length. Since daylength under natural conditions changes daily the melatonin rhythm, which adjusts to the photoperiod sends time of year information to the organism. The melatonin receptors which subserve the clock message sent by the pineal gland in the form of a melatonin cycle may reside in the biological clock itself, namely, the suprachiasmatic nuclei (SCN). The melatonin receptors that mediate seasonal changes in reproductive physiology are presumably those that are located on the pars tuberalis cells of the anterior pituitary gland. Besides these receptors which likely mediate clock and calendar information, melatonin receptors have been described in other organs. Interestingly, the distribution of melatonin receptors is highly species-specific. Whereas the clock and calendar information that the melatonin cycle imparts to the organism relies on cell membrane receptors, a fact that is of some interest considering the high lipophilicity of melatonin, recent studies indicate that other functions of melatonin may require no receptor whatsoever.
To study the prevalence, extent and evolution of high-grade prostatic intraepithelial neoplasia (HGPIN) in African-American and Caucasian men of a wide age range in order to help clarify the role this lesion may play in the racial differences of prostate cancer.
The lesion was documented in step-sectioned, entirely submitted prostates of two study populations: 525 autopsied men who died of trauma and 1,000 patients who had retropubic radical prostatectomy for clinically localized carcinoma of the prostate.
We found that HGPIN starts in young individuals and increases progressively with advancing age in both races but is more prevalent in African-Americans. Additionally, the more extensive form of HGPIN with multifocal or diffuse involvement of the gland appears at a younger age in African-Americans.
Microscopic foci of HGPIN can be documented in males in the 3rd and 4th decades with the lesion becoming more extensive in older men. The finding that HGPIN is both more prevalent and its more diffuse form appears earlier in African-Americans, indicates a potentially important role for this lesion in the race-related discrepancies associated with this disease.
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Deletions involving regions of chromosome 10 occur in the vast majority (> 90%) of human glioblastoma multiformes. A region at chromosome 10q23-24 was implicated to contain a tumour suppressor gene and the identification of homozygous deletions in four glioma cell lines further refined the location. We have identified a gene, designated MMAC1, that spans these deletions and encodes a widely expressed 5.5-kb mRNA. The predicted MMAC1 protein contains sequence motifs with significant homology to the catalytic domain of protein phosphatases and to the cytoskeletal proteins, tensin and auxilin. MMAC1 coding-region mutations were observed in a number of glioma, prostate, kidney and breast carcinoma cell lines or tumour specimens. Our results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.
The validity of melatonin as a prominent, naturally occurring oncostatic agent is examined in terms of its putative oncostatic mechanism of action, the correlation between melatonin levels and neoplastic activity, and the outcome of therapeutically administered melatonin in clinical trials. Melatonin's mechanism of action is summarized in a brief analysis of its actions at the cellular level, its antioxidative functions, and its indirect immunostimulatory effects. The difficulties of interpreting melatonin levels as a diagnostic or prognostic aid in cancer is illustrated by referral to breast cancer, the most frequently studied neoplasm in trials regarding melatonin. Trials in which melatonin was used therapeutically are reviewed, i.e., early studies using melatonin alone, trials of melatonin in combination with interleukin-2, and controlled studies comparing routine therapy to therapy in combination with melatonin. A table compiling the studies in which melatonin was used in the treatment of cancer in humans is presented according to the type of neoplasm. Melatonin's suitability in combination chemotherapy, where it augments the anticancer effect of other chemotherapeutic drugs while decreasing some of the toxic side effects, is described. Based on the evidence derived from melatonin's antiproliferative, antioxidative, and immunostimulatory mechanisms of action, from its abnormal levels in cancer patients and from clinical trials in which melatonin was administered, it is concluded that melatonin could indeed be considered a physiological anticancer substance. Further well-controlled trials should, however, be performed in order to find the link between its observed effects and the underlying mechanisms of action and to define its significance as a therapeutic oncostatic agent.
The PTEN gene encodes a dual-specificity phosphatase mutated in a variety of human cancers. PTEN germline mutations are found in three related human autosomal dominant disorders, Cowden disease (CD), Lhermitte-Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the role of PTEN in ontogenesis and tumour suppression, we disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Pten-/- ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal and mesodermal derivatives. Pten+/- mice and chimaeric mice derived from Pten+/- ES cells showed hyperplastic-dysplastic changes in the prostate, skin and colon, which are characteristic of CD, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.
Melatonin is a hormone primarily produced by the pineal gland at night and is suppressed by exposure to light. Experimental studies have indicated that melatonin may protect against cancer development. In the majority of totally blind people, melatonin is never suppressed by light exposure. The aim of this study was to test the hypothesis that blind people have a decreased cancer incidence, and that this effect is more pronounced in the totally blind than in the severely visually impaired. We identified a cohort of 1,567 totally blind and 13,292 severely visually impaired subjects and obtained information about cancer incidence from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) based on the number of person-years and incidence rates specific for national age, sex, and calendar year. Totally blind people had a lower incidence of all cancers combined [SIR = 0.69; 95% confidence interval (CI) = 0.59-0.82]. The risk reduction was observed in both men and women and was equally pronounced in hormone-dependent tumors as in other types of cancer. In the severely visually impaired, SIR was 0.95 (95% CI = 0.91-1.00). The findings support the hypothesis that blind people have a lower cancer incidence, although other explanations than the higher melatonin exposure must also be considered.
p27kip1 (p27) is a member of the universal cyclin-dependent kinase inhibitor (CDKI) family. p27 expression is regulated by cell contact inhibition and by specific growth factors, such as transforming growth factor (TGF)-beta. Since the cloning of the p27 gene in 1994, a host of other functions have been associated with this cell cycle protein. In addition to its role as a CDKI, p27 is a putative tumor suppressor gene, regulator of drug resistance in solid tumors, and promoter of apoptosis; acts as a safeguard against inflammatory injury; and has a role in cell differentiation. The level of p27 protein expression decreases during tumor development and progression in some epithelial, lymphoid, and endocrine tissues. This decrease occurs mainly at the post-translational level with protein degradation by the ubiquitin-proteasome pathway. A large number of studies have characterized p27 as an independent prognostic factor in various human cancers, including breast, colon, and prostate adenocarcinomas. Here we review the role of p27 in the regulation of the cell cycle and other cell functions and as a diagnostic and prognostic marker in human neoplasms. We also review studies indicating the increasingly important roles of p27, other CDKIs, and cyclins in endocrine cell hyperplasia and tumor development.
High-grade prostatic intraepithelial neoplasia (PIN) is most likely a precursor of prostate cancer and is frequently associated with it whereas the direct link between low-grade PIN and cancer is not established. The clinical evolution of isolated high-grade PIN has been the object of much concern because of the possibility of undiagnosed prostate cancer or the evolution of this premalignant lesion in invasive carcinoma. Parameters predictive of the later finding of prostate cancer on repeat biopsy in patients with PIN are of evident interest and we have reviewed our experience and recent data from the literature on this topic as well as on the clinical management of these patients. Low-grade PIN is not by itself a risk of later cancer found on repeat biopsy unless other factors such as PSA increase the cancer suspicion. Patients with low-grade PIN and high serum PSA should therefore undergo repeat biopsies. Patients with low-grade PIN and without additional factors should be followed. Patients with high-grade PIN should systematically be rebiopsied. If a second set is still consistent with PIN, they should undergo additional biopsies again within 3-6 months because they are likely to have an undiagnosed cancer.
Prostate cancer is the most common malignancy found in males; however, little is as yet known regarding what initiates the disease. The incidence is highest among American Blacks and lowest in the East Asian population. Subtypes of the disease include familial clustering and a hereditary form (9%) supporting genetic events to be involved in prostate cancer pathogenesis. Chromosomal abberations so far identified as being frequently occurring in this disease seem to be related to later phases of disease progression. However, research finding the responsible promoting genetic alteration is rapidly progressing. To explain the varied geographical distribution of the disease, the environment also has to be taken into account. Risk factors identified so far include obesity, animal fat, red meat consumption and certain toxins containing cadmium, while vegetables, cereals and vitamin D seem to be protective. It is reasonable to believe that, in the near future, we will be able to identify persons at risk of acquiring the disease and then inform them how to adjust their lifestyle to avoid early progression of the malignancy.
p27(Kip1) is a cyclin-dependent kinase inhibitor whose down-regulation has been observed in several tumour models, including breast, colorectal, and gastric carcinomas. The purpose of this study was to assess p27(Kip1) protein expression in normal and benign prostatic epithelia as well as the possible existence of abnormalities in prostate carcinoma progression. p27(Kip1) expression was immunohistochemically analysed in 51 normal tissue samples, 11 nodular hyperplasias (NH), 22 high-grade prostatic intraepithelial neoplasias (PIN), 56 localized prostate adenocarcinomas, and 19 metastases. Immunoblotting was performed in ten cases. Normal prostate epithelium and NH showed diffuse and intense p27(Kip1) nuclear expression in most cases. A significant p27(Kip1) down-regulation was observed in many carcinomas when compared with benign epithelium. Forty-seven cases (84 per cent) were low p27(Kip1) expressors (<50 per cent positive cells) and nine cases (16 per cent) were high p27(Kip1) expressors. p27(Kip1) down-regulation was also consistently seen in PIN. Fourteen out of 19 metastases (74 per cent) were low p27(Kip1) expressors. Six metastatic samples had their corresponding primary tumour analysed and three cases showed decreased expression in the metastasis. It is concluded that p27(Kip1) is constitutively expressed in normal and benign prostatic tissue. This expression is clearly down-regulated in neoplastic progression from the preinvasive lesions through invasive carcinoma and metastases and this therefore occurs in early stages of neoplastic transformation.
The aim of the present work was to study whether melatonin, at physiological concentrations, exerts its antiproliferative effects on MCF-7 human breast cancer cells by inducing the expression of some of the proteins involved in the control of the cell cycle. MCF-7 cells were cultured for 48 h in DMEM media containing either melatonin (1 nM) or the diluent (0.001% ethanol). At this concentration, after 48 hours of incubation, melatonin reduced the number of viable cells in relation to controls. The decreased cell proliferation was coincident with a significant increase in the expression of p53 as well as p21WAF1 proteins. These results demonstrate that melatonin inhibits MCF-7 cell proliferation by inducing an arrest of cell cycle dependent on an increased expression of p21WAF1 protein, which is mediated by the p53 pathway.
The guidelines for the curative treatment of prostate cancer presented by the German Society of Urology are discussed. They are based on the current knowledge of the outcomes of surgical and radiotherapeutic treatment for prostate cancer. Radical prostatectomy is recommended as the first-line treatment for organ-confined prostate cancer in patients with an individual life expectancy of at least 10 years. Radiotherapy can be considered as an alternative treatment modality, although current knowledge does not allow a definite assessment of the relative value of radiotherapy compared to radical prostatectomy. Locally advanced cT3 prostate cancer is overstaged in about 20% and curative treatment is possible in selected cases. Guidelines represent rules based on the available evidence. This implies that exceptions must be made whenever appropriate and that guidelines have to be reviewed regularly as new information becomes available.
Recent experimental evidence suggests that melatonin, the major pineal hormone, might possess oncostatic properties. The present experiments were performed to verify whether melatonin might modulate the growth of androgen-dependent prostate cancer cells (LNCaP) and to obtain information on its possible mechanism of action. We have shown that melatonin, when given in the nanomolar range, significantly inhibits the proliferation of LNCaP cells; moreover, the pineal gland hormone affects cell cycle distribution by inducing an accumulation of the cells in G0/G1 and a decrease in S phase. To investigate the mechanism of action of melatonin, by RT-PCR analysis we were able to demonstrate the expression, in prostate cancer cells, of a mRNA coding for the membrane Mel1a melatonin receptor. However, by radioreceptor assay, no detectable binding of 2-[125I]iodomelatonin could be observed in membrane preparations from these cells, suggesting that the levels of translation of the mRNA for Mel1a are possibly too low to mediate the antiproliferative action of the hormone. This hypothesis is further supported by the following observations: i) melatonin analogs, specifically acting through membrane receptors (i.e., 2-bromomelatonin), were completely ineffective in modulating prostate cancer cell proliferation; ii) melatonin failed to prevent forskolin-induced cAMP accumulation. These results indicate that melatonin, at nanomolar concentrations, exerts a direct antiproliferative action on androgen-dependent prostate cancer cells, significantly affecting their distribution throughout the cell cycle. Membrane receptors do not seem to be involved in the oncostatic action of the pineal gland hormone.
Melatonin, a pineal secretory product, has been shown to exert a direct anti-proliferative action on the androgen-sensitive LNCaP prostate cancer cell line through hitherto undefined mechanisms. In this communication, expression of mt1 melatonin receptor protein in human prostate cancer tissues and LNCaP cells was demonstrated by immunohisto(cyto)chemistry and western blotting, hence supporting the use of LNCaP cell line as a model for the study of melatonin signaling in prostate cancer cell growth. Using
H-thymidine incorporation assay, LNCaP cell proliferation was inhibited by 2-iodomelatonin, a high-affinity melatonin receptor agonist. Furthermore, melatonin inhibited
H-thymidine incorporation into LNCaP cells and attenuated 5α-dihydrotestosterone (DHT) or 17β-estradiol (E2)-induced stimulation of LNCaP cell proliferation at physiological and pharmacological concentrations. Similar concentration-dependent inhibition of sex steroid-induced stimulation of thymidine incorporation into LNCaP cells by 2-iodomelatonin was also observed. Interestingly, attenuation of sex steroid-stimulated calcium influx into LNCaP cells by pharmacological concentrations of melatonin was recorded, whereas 2-iodomelatonin had no effect on cytosolic calcium changes induced by sex steroids. In addition, proliferative and cytosolic calcium changes were associated with inhibition of total prostate-specific antigen (PSA) production by LNCaP cells at high physiological and pharmacological concentrations of melatonin. Our data suggest that activated mt1 receptor and attenuated sex steroid-induced calcium influx are two important mechanisms mediating the direct anti-proliferative action of melatonin on androgen-responsive human prostate cancer cells.
Potential involvement of the mt1 receptor in the antiproliferative action of melatonin on androgen-sensitive LNCaP cells, and melatonin-induced modulation of androgen-insensitive PC-3 cell growth, have been reported in vitro. The effects of melatonin on prostate cancer cell proliferation and their association with mt1 receptor expression were investigated in athymic nude mice xenograft models of LNCaP and PC-3 cells.
Daily saline or melatonin (4 microg/g body weight) was given to nude mice before or after tumor cell inoculation. Tumor volume was measured periodically, and expression of PCNA, cyclin A, PSA, and mt1 receptor was assessed by immunohisto(cyto)chemistry and/or Western blotting.
Melatonin inhibited the growth of LNCaP tumors, without affecting the growth of PC-3 xenografts, in nude mice. It induced significant decreases in the expression of PCNA, cyclin A, and PSA in LNCaP tumors. Expression of mt1 receptor protein was demonstrated in LNCaP cells, but not in PC-3 cells, both in vivo and in vitro.
The antiproliferative action of melatonin on LNCaP tumor growth was demonstrated in vivo, and its association with mt1 receptor protein expression suggests the potential involvement of the receptor in the antitumor activity of the pineal gland hormone.