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Cancer metastasis: Mechanisms of inhibition by melatonin
Abstract
Melatonin is a naturally occurring molecule secreted by the pineal gland and known as a gatekeeper of circadian clocks. Mounting evidence indicates that melatonin, employing multiple and interrelated mechanisms, exhibits a variety of oncostatic properties in a myriad of tumors during different stages of their progression. Tumor metastasis, which commonly occurs at the late stage is responsible for the majority of cancer deaths; metastases lead to the development of secondary tumors distant from a primary site. In reference to melatonin, the vast majority of investigations have focused on tumor development and progression at the primary site. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clinical observations; emphasis is placed on the impact of both cancer and non-neoplastic cells within the tumor microenvironment. Due to the broad range of melatonin's actions, the mechanisms underlying its ability to interfere with metastases are numerous. These include modulation of cell-cell and cell-matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, epithelial-mesenchymal transition, and angiogenesis. The evidence discussed herein will serve as a solid foundation for urging basic and clinical studies on the use of melatonin to understand and control metastatic diseases. This article is protected by copyright. All rights reserved.
... Melatonin, a hormone mainly secreted from the pineal gland, has been proven to possess extensive biological activities including circadian rhythms regulation, anti-oxidation, anti-inflammation and immunoregulation [1][2][3][4][5]. As to cancer, mounting evidence indicates that melatonin exhibits oncostatic features at the initiation, progression and metastasis phases through multiple and interrelated mechanisms [5][6][7][8][9][10][11]. Esophageal squamous cell carcinoma (ESCC) is ranked as the 6th leading cause of cancer-related deaths in the world [12,13]. ...
... Previous studies revealed melatonin has significant inhibitory effects on numerous cancers [5][6][7][8][9]. Melatonin exerted anticancer actions in almost every stage of tumor generation and development through the joint effect of multiple functions, such as inhibiting proliferation, angiogenesis and metastasis, affecting aerobic metabolism, and enhancing chemotherapy efficiency [5][6][7][8][9][10][11]. ...
... Previous studies revealed melatonin has significant inhibitory effects on numerous cancers [5][6][7][8][9]. Melatonin exerted anticancer actions in almost every stage of tumor generation and development through the joint effect of multiple functions, such as inhibiting proliferation, angiogenesis and metastasis, affecting aerobic metabolism, and enhancing chemotherapy efficiency [5][6][7][8][9][10][11]. ...
Background:
Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.
Methods:
ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes' expression and prognosis of ESCC.
Results:
Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan-Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.
Conclusions:
Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.
... Structurally, melatonin is an indolamine (N-acetyl-5-methoxytryptamine), with the pineal gland being the site of its circadian production (3). In addition to the pineal gland, melatonin is present in many other organs where it is also likely synthesized (4). In the gastrointestinal tract, its major activities are mediated by its membrane receptors, i.e., MT1 and MT2 while the receptor independent actions are also involved in the activities of gut and adnexa (5). ...
... Moreover, melatonin also inhibits HIF-1 and STAT3 signaling pathway in HepG2 liver cancer cells (68). Melatonin also interferes with metastases via modulation of cell-cell and cell-matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, reducing the epithelial-mesenchymal transition, and angiogenesis (4). The antiinflammatory activities of melatonin are well documented. ...
Several factors impact the mortality rate of patients with gastrointestinal cancers including late diagnosis, metastases to distance sites, and lack of efficacy of the conventional therapies. To reduce mortality rate, the novel effective remedies should be explored. Melatonin is an anti-inflammatory, antioxidant and oncostatic molecule and has been showed potential in controlling various malignancies. In the gastrointestinal tract, melatonin plays an important role via its membrane receptors of MT1 and MT2. It can diminish esophageal lesions resulting from acid–pepsin–bile contact and also inhibits expression of myosin light chain kinase as well as reduces its activity by regulating extracellular signal-transduction of protein kinase. The aim of the present study was to review the critical functions of melatonin in the prevention and treatment of esophageal squamous cell carcinoma including its influence on gastrointestinal pathology, oncostatic role and potential mechanisms. Particularly, the inhibitory function of melatonin on esophageal squamous cell carcinoma and its therapeutic effects are summarized. We suggest that melatonin co-treatment will enhance the efficacy of conventional treatments and survival times in patients with esophageal squamous cell carcinoma.
... Melatonin reduces the invasiveness of human cancers including breast cancer [45e48], prostate cancer [49], liver cancer [43,50], oral cancer [51], lung cancer [52], ovarian cancer [53], etc. [54,55]. The anti-metastatic effects of melatonin are achieved by an increase in the expression of cell surface adhesion molecules E-cadherin, b1integrin, and occludin, the downregulation of integrin molecules, reduction in the expression or activity of the matrix metalloproteinase, inhibition of the cytoskeleton rearrangement, induction of epithelial to mesenchymal transition, and angiogenesis suppression [54]. ...
... Melatonin reduces the invasiveness of human cancers including breast cancer [45e48], prostate cancer [49], liver cancer [43,50], oral cancer [51], lung cancer [52], ovarian cancer [53], etc. [54,55]. The anti-metastatic effects of melatonin are achieved by an increase in the expression of cell surface adhesion molecules E-cadherin, b1integrin, and occludin, the downregulation of integrin molecules, reduction in the expression or activity of the matrix metalloproteinase, inhibition of the cytoskeleton rearrangement, induction of epithelial to mesenchymal transition, and angiogenesis suppression [54]. More importantly, overexpression of the MT1 receptor can cause an increase in the anti-invasive response of cancer cells to melatonin. ...
Melatonin, the major secretory product of the pineal gland, not only regulates circadian rhythms, mood, and sleep but also has actions in neoplastic processes which are being intensively investigated. Melatonin is a promising molecule which considered a differentiating agent in some cancer cells at both physiological and pharmacological concentrations. It can also reduce invasive and metastatic status through receptors MT1 and MT2 cytosolic binding sites, including calmodulin and quinone reductase II enzyme, and nuclear receptors related to orphan members of the superfamily RZR/ROR. Melatonin exerts oncostatic functions in numerous human malignancies. An increasing number of studies report that melatonin reduces the invasiveness of several human cancers such as prostate cancer, breast cancer, liver cancer, oral cancer, lung cancer, ovarian cancer, etc. Moreover, melatonin's oncostatic activities are exerted through different biological processes including antiproliferative actions, stimulation of anti-cancer immunity, modulation of the cell cycle, apoptosis, autophagy, the modulation of oncogene expression, and via antiangiogenic effects. This review focuses on the oncostatic activities of melatonin that targeted cell cycle control, with special attention to its modulatory effects on the key regulators of the cell cycle, apoptosis, and telomerase activity.
... Melatonin reduces the invasiveness of human cancers including breast cancer [45e48], prostate cancer [49], liver cancer [43,50], oral cancer [51], lung cancer [52], ovarian cancer [53], etc. [54,55]. The anti-metastatic effects of melatonin are achieved by an increase in the expression of cell surface adhesion molecules E-cadherin, b1integrin, and occludin, the downregulation of integrin molecules, reduction in the expression or activity of the matrix metalloproteinase, inhibition of the cytoskeleton rearrangement, induction of epithelial to mesenchymal transition, and angiogenesis suppression [54]. ...
... Melatonin reduces the invasiveness of human cancers including breast cancer [45e48], prostate cancer [49], liver cancer [43,50], oral cancer [51], lung cancer [52], ovarian cancer [53], etc. [54,55]. The anti-metastatic effects of melatonin are achieved by an increase in the expression of cell surface adhesion molecules E-cadherin, b1integrin, and occludin, the downregulation of integrin molecules, reduction in the expression or activity of the matrix metalloproteinase, inhibition of the cytoskeleton rearrangement, induction of epithelial to mesenchymal transition, and angiogenesis suppression [54]. More importantly, overexpression of the MT1 receptor can cause an increase in the anti-invasive response of cancer cells to melatonin. ...
Melatonin, the major secretory product of the pineal gland, not only regulates circadian rhythms, mood, and sleep but also has actions in neoplastic processes which are being intensively investigated. Melatonin is a promising molecule which considered a differentiating agent in some cancer cells at both physiological and pharmacological concentrations. It can also reduce invasive and metastatic status through receptors MT1 and MT2 cytosolic binding sites, including calmodulin and quinone reductase II enzyme, and nuclear receptors related to orphan members of the superfamily RZR/ROR. Melatonin exerts oncostatic functions in numerous human malignancies. An increasing number of studies report that melatonin reduces the invasiveness of several human cancers such as prostate cancer, breast cancer, liver cancer, oral cancer, lung cancer, ovarian cancer, etc. Moreover, melatonin's oncostatic activities are exerted through different biological processes including antiproliferative actions, stimulation of anti-cancer immunity, modulation of the cell cycle, apoptosis, autophagy, the modulation of oncogene expression, and via antiangiogenic effects. This review focuses on the oncostatic activities of melatonin that targeted cell cycle control, with special attention to its modulatory effects on the key regulators of the cell cycle, apoptosis, and telomerase activity.
... This action of melatonin has linked it to a very wide variety of cancer types, e.g., breast, prostate, lung, cervical, colorectal, liver, melanoma, leukemia, several childhood cancers, etc. Moreover, melatonin has been shown to be involved in tumor initiation, progression and metastasis [10,12,13,[19][20][21][22]. ...
... Melatonin, an endogenously produced molecule, has been repeatedly proven to inhibit many experimental cancer types in multiple organs [10,12,13,17,22,54]. Numerous molecular mechanisms have been proposed to explain the ability of melatonin to resist the growth of the tumors investigated, e.g., suppression of growth factor uptake [55], estrogen inhibition [56], toll-like receptor inhibition [57], promotion of antioxidant activity [58], reduction of tumor angiogenesis [59,60], attenuation of the HER2 signaling pathway [61], etc. ...
Melatonin has a long history of studies which confirm its ability to inhibit cancer growth. Melatonin is present in high concentrations in the mitochondria of normal cells but is likely absent from the mitochondria of cancer cells, at least when isolated from tumors harvested during the day. Herein, we hypothesize that melatonin’s absence from cancer cell mitochondria prevents these organelles from metabolizing pyruvate to acetyl coenzyme A (acetyl-CoA) due to suppression of the activity of the enzyme pyruvate dehydrogenase complex (PDC), the enzyme that catalyzes the conversion of pyruvate to acetyl-CoA. This causes cancer cells to metabolize glucose to lactate in the cytosol (the Warburg effect). Since cancer cell mitochondria can take up nighttime pineal-derived melatonin from the blood, the indoleamine predictably promotes the conversion of pyruvate to acetyl-CoA in the mitochondria during the night. Thus, while cancer cells exhibit a typical cancer phenotype during the day, at night cancer cells have a more normal cell phenotype. Via similar actions, melatonin probably overcomes the insensitivity of cancers to chemotherapies. Hopefully, the hypothetical processes proposed herein will soon be experimentally tested.
... Additionally, melatonin has multiple anti-cancer properties such as anti-proliferation, anti-angiogenesis, immune system modulation, and apoptotic activities [12][13][14][15]. More interestingly, studies have demonstrated that melatonin modulated hypoxia-induced tumorigenesis [16][17][18], and co-administration of melatonin in combination with other therapeutic compounds increased the effectiveness of those treatments [19][20][21]. This review aims to describe the pathways involved in hypoxia-induced cancer development and more importantly explain how melatonin can possibly inhibit hypoxia-mediated tumor progression. ...
... Melatonin also suppresses oxidative-stress-induced detachment of cancer cells via overexpressing the β1 integrin and down-regulation of ROS-αvβ3 integrin-FAK/Pyk2 signaling pathway [95,96]. HIF-1α overexpresses RhoA and Rho kinase 1 (ROCK1) leading to actin-myosin contraction and cell motility [17]. Moreover, Rho triggers the focal adhesion kinase (FAK) signaling pathway and consequently induces motility and an invasive phenotype of hypoxic cancer cells [97]. ...
Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.
... In addition, melatonin also has a regulatory effect on the human cardiovascular system, respiratory system, digestive system, and urinary system. It is also involved in immunity, weight loss, and anti-inflammatory and anti-cancer functions [23][24][25]. ...
... From a local perspective, gastrointestinal tissue can synthesize and secrete a certain level of melatonin, but it is not excessively released into the blood. It mainly affects the activities of surrounding cells and self-secreting cells through paracrine and autocrine pathways [25]. The synthesis and rapid absorption of this local melatonin enhance intestinal immune activity, prevents harmful compounds or toxins from being produced by the gut microbiota, and inhibits colon diseases and dysplasia. ...
Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. The occurrence and development of CRC are complicated processes. Obesity and dysbacteriosis have been increasingly regarded as the main risk factors for CRC. Understanding the etiology of CRC from multiple perspectives is conducive to screening for some potential drugs or new treatment strategies to limit the serious side effects of conventional treatment and prolong the survival of CRC patients. Melatonin, a natural indoleamine, is mainly produced by the pineal gland, but it is also abundant in other tissues, including the gastrointestinal tract, retina, testes, lymphocytes, and Harder's glands. Melatonin could participate in lipid metabolism by regulating adipogenesis and lipolysis. Additionally, many studies have focused on the potential beneficial effects of melatonin in CRC, such as promotion of apoptosis; inhibition of cell proliferation, migration, and invasion; antioxidant activity; and immune regulation. Meaningfully, gut microbiota is the main determinant of all aspects of health and disease (including obesity and tumorigenesis). The gut microbiota is of great significance for understanding the relationship between obesity and increased risk of CRC. Although the current understanding of how the melatonin-mediated gut microbiota coordinates a variety of physiological and pathological activities is fairly comprehensive, there are still many unknown topics to be explored in the face of a complex nutritional status and a changeable microbiota. This review summarizes the potential links among melatonin, lipid metabolism, gut microbiota, and CRC to promote the development of melatonin as a preventive and therapeutic agent for CRC.
... After hydroxylation and decarboxylation, tryptophan synthesizes serotonin (5hydroxytryptamine) and this process is regulated by tryptophan hydroxylase and decarboxylase [8]. Serotonin is then acetylated, methylated, and converted to melatonin in the pineal gland [9]. Recently, accumulating evidence has revealed that melatonin suppresses tumorigenesis, metastasis, and drug resistance in multiple cancers [10][11][12]. ...
... Melatonin is a well-known hormone that is generated by the pineal gland [29]. Recently, the antitumor effects of melatonin have gained significant attention and numerous studies reveal that melatonin exerts growth inhibition on tumor cells [9,30,31]. The potential mechanisms include stimulation of apoptosis, regulation of cancer immunity, cell cycle arrest, and modulation of prosurvival signaling [32]. ...
Background:
Melatonin is an indolic compound mainly secreted by the pineal gland and plays a vital role in the regulation of circadian rhythms and cancer therapy. However, the effects of melatonin in gallbladder cancer (GBC) and the related mechanism remain unknown.
Methods:
In this study, the antitumor activity of melatonin on gallbladder cancer was explored both in vitro and in vivo. After treatment with different concentrations of melatonin, the cell viability, migration, and invasion of gallbladder cancer cells (NOZ and GBC-SD cells) were evaluated by CCK-8 assay, wound healing, and Transwell assay.
Results:
The results showed that melatonin inhibited growth, migration, and invasion of gallbladder cancer cells. Subsequently, the assays suggested that melatonin significantly induced apoptosis in gallbladder cancer cells and altered the expression of the apoptotic proteins, including Bax, Bcl-2, cytochrome C, cleaved caspase-3, and PARP. Besides, the intracellular reactive oxygen species (ROS) was found to be upregulated after melatonin treatment in gallbladder cancer cells. Melatonin was found to suppress the PI3K/Akt/mTOR signaling pathway in a time-dependent manner by inhibiting the phosphorylation of PI3K, Akt, and mTOR. Treatment with N-acetyl-L-cysteine (NAC) or 740 Y-P remarkably attenuated the antitumor effects of melatonin in NOZ and GBC-SD cells. Finally, melatonin suppressed the growth of GBC-SD cells in an athymic nude mice xenograft model in vivo.
Conclusions:
Our study revealed that melatonin could induce apoptosis by suppressing the PI3K/Akt/mTOR signaling pathway. Therefore, melatonin might serve as a potential therapeutic drug in the future treatment of gallbladder cancer.
... Invasion and metastasis, the major mechanisms of cancer development, refer to the processes in which cancer cells enter the circulatory system through intravasation and form metastatic cancer in adjacent tissues through extravasation (Su et al., 2017). Therefore, preemptively blocking invasion and metastasis of cancer to inhibit cell metastasis, and in particular, a method of reducing cell mobility is necessary and is considered an effective strategy (Gam et al., 2021b). ...
... However, the concept of mesenchymal-derived osteosarcoma cells in EMT with the capability to initiate the metastasis cascade has been further applied in the past decade [54][55][56][57]. ...
Curcumin is a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties but is concerned about poor solubility in water, absorption, and metabolic stability. Potent metastatic osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. It is responsible for low survival rates because of its high rate of metastasis to the lungs. To improve poor bioavailability, numerous curcumin analogs were developed to possess anticancer characteristics through a variety of biological pathways involved in cytotoxicity, proliferation, autophagy, sensitizing chemotherapy, and metastases. This review provides an overview of their various pharmacological functions, molecular mechanisms, and therapeutic potential as a remedy for human osteosarcoma. To enhance therapeutic efficacy, several liposomal nanoparticles, nanocarriers, multifunctional micelles, and three-dimensional printed scaffolds have also been developed for the controlled delivery of curcumin targeting human osteosarcoma cells. Consequently, curcumin and several potential analogs and delivery formulations are optimistic candidates to improve the currently available strategy for human osteosarcoma. However, further insight into the mechanism of action of promising curcumin analogs and the development of carriers in clinical trials of osteosarcoma needs to be investigated to improve their overall potency and clinical utility, in particular the anti-metastatic effect.
... Thus, improving our knowledge of the molecular basis of disseminated NPC is central to the development of new treatment options for ultimately alleviating this aggressive malignancy. Cancer cell invasion and metastasis are hallmarks of tumors that require malignant cells to move from the original site and propagate at a remote location [6,7]. The metastatic dissemination of NPC comprises various molecular and cellular processes carried out by both malignant and non-malignant cells within the tumor microenvironment [8][9][10][11]. ...
Cancer metastasis is a main cause of failure in treating subjects with nasopharyngeal carcinoma (NPC) and is frequently linked to high death rates. EF-24, an analog of curcumin, has exhibited many anti-cancer properties and enhanced bioavailability over curcumin. Nevertheless, the effects of EF-24 on the invasiveness of NPC are poorly understood. In this study, we demonstrated that EF-24 effectively inhibited TPA-induced motility and invasion responses of human NPC cells but elicited very limited cytotoxicity. In addition, the TPA-induced activity and expression of matrix metalloproteinase-9 (MMP-9), a crucial mediator of cancer dissemination, were found to be reduced in EF-24-treated cells. Our reporter assays revealed that such a reduction in MMP-9 expression by EF-24 was transcriptionally mediated by NF-κB via impeding its nuclear translocation. Further chromatin immunoprecipitation assays displayed that the EF-24 treatment decreased the TPA-induced interaction of NF-κB with the MMP-9 promoter in NPC cells. Moreover, EF-24 inhibited the activation of JNK in TPA-treated NPC cells, and the treatment of EF-24 together with a JNK inhibitor showed a synergistic effect on suppressing TPA-induced invasion responses and MMP-9 activities in NPC cells. Taken together, our data demonstrated that EF-24 restrained the invasiveness of NPC cells through the transcriptional suppression of MMP-9 gene expression, implicating the usefulness of curcumin or its analogs in controlling the spread of NPC.
... Additionally, melatonin seems to intervene in processes related to the immune system since it can be influenced by light signals through the neuroendocrine. In this way, melatonin acts as an anti-inflammatory, antioxidant and neuroprotective agent in many diseases such as neurodegenerative (dementia, Alzheimer, Parkinson), cardiovascular, obesity, cancer and other dysfunctions [29][30][31][32][33][34][35][36][37][38]. In addition, melatonin has been used to combat animal and human viral diseases, such as Venezuelan ...
Melatonin is a multifunctional and ubiquitous molecule. In animals, melatonin is a hormone that is involved in a wide range of physiological activities and is also an excellent antioxidant. In plants, it has been considered a master regulator of multiple physiological processes as well as of hormonal homeostasis. Likewise, it is known for its role as a protective biomolecule and activator of tolerance and resistance against biotic and abiotic stress in plants. Since infections by pathogens such as bacteria, fungi and viruses in crops result in large economic losses, interest has been aroused in determining whether melatonin plays a relevant role in plant defense systems against pathogens in general, and against viruses in particular. Currently, several strategies have been applied to combat infection by pathogens, one of them is the use of eco-friendly chemical compounds that induce systemic resistance. Few studies have addressed the use of melatonin as a biocontrol agent for plant diseases caused by viruses. Exogenous melatonin treatments have been used to reduce the incidence of several virus diseases, reducing symptoms, virus titer, and even eradicating the proliferation of viruses such as Tobacco Mosaic Virus, Apple Stem Grooving Virus, Rice Stripe Virus and Alfalfa Mosaic Virus in tomato, apple, rice and eggplant, respectively. The possibilities of using melatonin as a possible natural virus biocontrol agent are discussed.
... Patients may be less able to complete normally important personal care routines (e.g., shaving). Others (Su et al., 2017) may no longer recognize an individual as the same person. This can cause patients to feel shame or that they are not lovable. ...
This study aimed to show how cancer has affected the economic and psychosocial aspects of patients’ livelihoods in Nakuru County. The study adopted descriptive survey design and draw on a quantitative inquiry. The sample size, determined by Fishers method, were 245 patients and 10 medical officers (medical superintendent, oncologists and nurses) drawn from the Nakuru County Teaching and referral Hospital. The research instruments employed were the questionnaire and interview schedules. Before the actual data collection, piloting of questionnaires and the interview schedule was done in Moi Teaching and Referral Hospital in Uasin Gishu County. Data analysis followed both parametric and non-parametric approaches. Data was presented using graphs, tables and scatter diagrams. The findings of the study suggest a strong association of cancer with loss of income (????16, 0.01 = 40.101) and a significant increase in medical expenditure (????12, 0.01 = 66.789). Similarly, it was shown that cancer patients were impacted both socially and economically by cancer type (????12, 0.033 = 22.46) and duration of treatment. The results from the study will contribute immensely to the development of new strategies to improve patients’ economic status in the management of cancer within Nakuru county and Kenya in general.
... Melatonin (MT) is one of the hormones synthesized, stored, and secreted by the pineal gland [12,13]. Its secretion has a distinct circadian rhythm which is inhibited during the day and promoted at night [14,15]. ...
It was found recently that iron overload can cause osteoporosis in rats. Through in vitro and in vivo experimentations, the purpose of the present study was to validate and confirm the inhibitory effects of melatonin on iron death of osteoporosis and its role in bone microstructure improvements. Melatonin (100 mol/L) was administered to MC3T3-E1 cells induced by iron overload in vitro for 48 hours. The expression of cleaved caspase-3 and cleaved PARP and the production of ROS (reactive oxygen species) and mitochondrial damage were all exacerbated by iron overload. On the other hand, melatonin restored these impacts in MC3T3-E1 cells produced by iron overload. By evaluating the expression of PI3K/AKT/GSK-3β/P70S6k signaling pathway-related proteins (RUNX2, BMP2, ALP, and OCN) using RT-PCR and Western blot, osteogenic-related proteins were identified. Alizarin red S and alkaline phosphatase were utilized to evaluate the osteogenic potential of MC3T3-E1 cells. Melatonin significantly improved the osteogenic ability and phosphorylation rates of PI3K, AKT, GSK-3β, and P70S6k in iron overload-induced MC3T3-E1 cells. In vivo, melatonin treated iron overload-induced osteoporotic bone defect in rats. Rat skeletal microstructure was observed using micro-CT and bone tissue pathological section staining. ELISA was utilized to identify OCN, PINP, CTX-I, and SI in the serum of rats. We discovered that melatonin increased bone trabecular regeneration and repair in osteoporotic bone defects caused by iron overload. In conclusion, melatonin enhanced the osteogenic ability of iron overload-induced MC3T3-E1 cells by activating the PI3K/AKT/GSK-3β/P70S6k signaling pathway and promoting the healing of iron overload-induced osteoporotic bone defects in rats.
... The treatment of tumors with melatonin improved chemo-and radiotherapy sensitivity, acting as a synergistic molecule in the control of cancer cells. Additionally, melatonin mitigates acute damage to normal cells, protecting them against drug toxicity, possibly by enhancing immune responses [20][21][22]. Among the dysfunctions and diseases where the beneficial effects of melatonin have been studied are neurological ones, such as Alzheimer's, Parkinson's, fibromyalgia, depression, attention-deficit hyperactivity disorder, autism, and migraines; cardiovascular health problems, including hypercholesterolemia, hypertension, metabolic syndrome, and glycemic imbalance; gastrointestinal health problems, such as gastroesophageal reflux, ulcers, and irritable bowel syndrome; immunological health problems, such as multiple sclerosis, autoimmune responses (athletic stress, toxic stress, psoriasis, etc.), sepsis, COVID-19, etc. [3,[23][24][25][26]; and also osteopenia [27], sarcopenia [28], pre-eclampsia, fertility, polycystic ovarian syndrome, and menopause, among others [29][30][31][32]. ...
Melatonin dietary supplements are widely consumed worldwide, with developed countries as the largest consumers, with an estimated annual growth rate of approximately 10% until 2027, mainly in developing countries. The wide use of melatonin against sleep disorders and particular problems, such as jet lag, has been added to other applications, such as anti-aging, anti-stress, immune system activation, anticancer, and others, which have triggered its use, normally without a prescription. The chemical industry currently covers 100% of the needs of the melatonin market. Motivated by sectors with more natural consumption habits, a few years ago, the possibility of obtaining melatonin from plants, called phytomelatonin, arose. More recently, the pharmaceutical industry has developed genetically modified microorganisms whose ability to produce biological melatonin in bioreactors has been enhanced. This paper reviews the aspects of the chemical and biological synthesis of melatonin for human consumption, mainly as dietary supplements. The pros and cons of obtaining melatonin from microorganisms and phytomelatonin from plants and algae are analyzed, as well as the advantages of natural melatonin, avoiding unwanted chemical by-products from the chemical synthesis of melatonin. Finally, the economic and quality aspects of these new products, some of which are already marketed, are analyzed.
... The tissue inhibitor of metalloproteinases (TIMPs), including TIMP1, 2, 3, and 4, are endogenous regulators of matrix metalloproteinases (MMPs) [5][6][7][8]. TIMPs have been implicated in extracellular matrix degradation, tissue remodeling, cancer cell invasion, and metastasis, and an imbalance between TIMPs and MMPs activity may have implications for cancer progression [9][10][11]. TIMP3 is unique among the mammalian TIMPs, differing from other TIMPs in that it is tightly bound to the extracellular matrix and it has a broader inhibitory activity against MMPs and inhibits it's closely related a disintegrin and metalloproteinases [12]. ...
The tissue inhibitors of metalloproteinases-3 (TIMP3) are not only endogenous regulators of matrix metalloproteinases (MMPs), but also induce apoptosis and inhibit endothelial cell migration and angiogenesis. The focus of this study was to investigate the relationship between TIMP3 genetic polymorphisms and biochemical recurrence and clinicopathological features of prostate cancer. The TIMP3 rs9619311, rs9862, and rs11547635 genetic polymorphisms were analyzed by real-time polymerase chain reaction to determine their genotypic distributions in 579 patients with prostate cancer. This study found that individuals with the TIMP3 rs9619311 TC or TC + CC genotypes have a significantly higher risk of biochemical recurrence of prostate cancer (p = 0.036 and 0.033, respectively). Moreover, in the multivariate analysis, our results showed that pathologic Gleason grade, pathologic T stage, seminal vesicle invasion, lymphovascular invasion, and TIMP3 rs9619311 were associated with increased odds of biochemical recurrence. Patients with a PSA concentration under 7 ng/mL that were found to have the TIMP3 rs9619311 genetic polymorphism were associated with Gleason total score upgrade (p = 0.012) and grade group upgrade (p = 0.023). Compared with the CC homozygous, the TIMP3 rs9862 CT + TT polymorphic variant was found to be associated with clinically advanced tumor stage (p = 0.030) and Gleason total score upgrade (p = 0.002) in prostate cancer patients. In conclusion, the results of our study demonstrated that the TIMP3 rs9619311 genetic polymorphism was significantly associated with susceptibility to biochemical recurrence of prostate cancer. TIMP3 genetic polymorphisms, especially rs9619311, can serve as key predictors of biochemical recurrence and disease prognosis of prostate cancer.
... Through Tie2/PI3K/AKT signaling, EGFL6 plays a role in tumor angiogenesis. Cell adhesion, angiogenesis, migration, invasion, and adherent independent growth are all mechanisms that contribute to tumor invasion and metastasis [36][37][38][39]. ...
The epidermal growth factor (EGF) superfamily includes the protein 6 with an epidermal growth factor-like protein (EGFL6). EGFL6 has a signal peptide domain with an amino terminus and a MAM domain with a carboxy terminus. There are four whole EGF-like repeat regions and one partial EGF-like repeat region. Three of these regions include calcium-binding structures and an arg-gly-asp (RGD) integrin interaction motif. The epidermal growth factor-like (EGFL) and EGF domains have identical amino acid residues. Cell division, differentiation, mortality, cell adhesion, and migration are all affected by EGFL6. EGFL proteins are involved in a broad range of biological activities, making it important in tumor development and angiogenesis. We highlighted the latest development of EGFL6 research on tumor proliferation, invasion, and migration in this review.
... Melatonin shows antimetastatic activity by targeting the cell cycle and apoptosis, by preventing crosstalk between cells, the cell matrix and cell cytoskeletons, and by inhibiting EMT [39]. Several studies have addressed the capacity of melatonin to suppress EMT [18]. In one investigation, melatonin inhibited the invasive capacity of BCa cells by regulating the expression of E-cadherin and β-integrin [40]. ...
Melatonin, a naturally biosynthesized molecule secreted by the pineal gland, exhibits antitumor activities against several different types of cancer. The mechanisms of action of melatonin against tumor progression involve cellular apoptosis, antimetastatic activity, antioxidant and mutagenic effects, antiangiogenic activity, and the restoration of cancer immune surveillance. Melatonin has anticancer activity when administered alone or in combination with standard chemotherapeutic agents, with measurable improvements seen in the clinical endpoints of tumor regression and patient survival. However, scant clinical evidence supports the use of melatonin in bladder cancer treatment. Our study has found that melatonin treatment suppresses the bladder cancer cell migratory ability by inhibiting the epithelial-mesenchymal transition (EMT) process, which appears to be linked to melatonin-induced decreases in bladder cancer cell autophagy. Finally, an evaluation of in vivo melatonin-induced antitumor effects in an orthotopic animal model of bladder cancer indicated that melatonin treatment slightly prolonged the survival of tumor-bearing mice. Our study offers novel insights into the use of melatonin in bladder cancer treatment.
... For metastasis to occur, cancer cells must leave their main sites, circulate in the blood, withstand vascular pressure, adapt to the new cellular environment of the secondary sites, and withstand attacks from immune cells [6][7][8]. Metastasis is the primary cause of death in more than 90% of patients with cancer [9][10][11]. Although cancer metastasis is a primary cause of cancer treatment failure and subsequent death, little is known about it. ...
Cervical cancer has a poor prognosis and is the fourth most common cancer among women. Dihydromyricetin (DHM), a flavonoid compound, exhibits several pharmacological activities, including anticancer effects; however, the effects of DHM on cervical cancer have received insufficient research attention. This study examined the antitumor activity and underlying mechanisms of DHM on human cervical cancer. Our results indicated that DHM inhibits migration and invasion in HeLa and SiHa cell lines. Mechanistically, RNA sequencing analysis revealed that DHM suppressed S100A4 mRNA expression in HeLa cells. Moreover, DHM inhibited the protein expressions of β-catenin and GSK3β through the regulated extracellular-signal-regulated kinase (ERK)1/2 signaling pathway. By using the ERK1/2 activator, T-BHQ, reverted β-catenin and S100A4 protein expression and cell migration, which were reduced in response to DHM. In conclusion, our study indicated that DHM inhibited cell migration by reducing the S100A4 expression through the ERK1/2/β-catenin pathway in human cervical cancer cell lines.
... Melatonin (N-acetyl-5-methoxy-tryptamine) is a molecule produced and released from the pineal gland. Apart from sleep and circadian regulations, melatonin displays inhibitory properties during tumor progression (4)(5)(6). The prognosis of pineal gland metastasis is poor because it generally occurs in the late course of widely metastatic systemic cancer (7). ...
Pineal bez metastazları oldukça nadirdir. Çalışmamızın amacı, pineal bez metastazlarının manyetik rezonans görüntüleme bulgularını değerlendirmektir. Bu çalışmada Eylül 2010 ile Aralık 2019 tarihleri arasında hastane/ radyoloji arşivindeki beyin manyetik rezonans görüntülemelerinin raporları retrospektif olarak tarandı. Olgular belirlendikten sonra, hastaların cinsiyet, yaş, tanı, sağkalım süresi gibi özellikleri ve boyut (en büyük kesit çap), T1 ağırlıklı, T2 ağırlıklı sinyaller, kontrast tutulumu, ek beyin metastatik tutulum alanları gibi özellikler değerlendirildi. Araştırmamızda pineal metastazlı 7 hasta tespit edildi. Altta yatan maligniteler akciğer (N 2), meme (N 2), prostat kanseri (N 1), nöroblastom (N 1), non-Hodgkin lenfoma (N 1) idi. Pineal metastaz saptandıktan sonra ortalama yaşam süresi 3.14 aydı. Lezyonların boyutları 0.8 ile 1.8 cm arasında değişiyordu. Altı tümör, hem T1 ağırlıklı hem de T2 ağırlıklı olarak gri cevhere göre izointens idi. Biri T1 ağırlıklı ve T2 ağırlıklı görüntülerde heterojen sinyal intensitesi gösterdi. 7 tümörden 6'sı homojen solid kontrastlanma gösterirken, bir tümör nekroza bağlı heterojen kontrastlanma gösterdi. İki hastada leptomeningeal, bir hastada hipofiz sapı, bir hastada parankim, bir hastada kalvaryum-dural metastaz vardı. Kalan 3 hastada ise beyinde eşlik eden metastaz izlenmedi. Bilinen malignitesi olan hastalarda pineal lezyonların varlığı metastatik tutulum şüphesini artırmalıdır.
... OSCC is generally detected in the middle or late stages, due to non-specific early clinical symptoms. Despite recent advancements in the treatment of OSCC, the 5-year survival rate remains low [44,45]. OSCC is a malignant tumor affecting the head and neck region, which has also been shown to harm oral epithelial cells [46]. ...
Oral squamous cell carcinoma (OSCC) is particularly prevalent in Taiwan. The goal of this study was to determine the clinicopathological role of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) proteins as an indicator of clinical outcomes in OSCC patients. In this study, immunohistochemical (IHC) analysis was used to examine IGF2BP2 protein expression in 244 OSCC patients. We investigated the relationships among IGF2BP2 expression, clinicopathological variables, and patient survival. Our results showed that IGF2BP2 cytoplasmic protein expression was significantly correlated with lymph node metastasis, cancer stage, and patient survival. Kaplan-Meier survival curves revealed that elevated cytoplasmic IGF2BP2 expression levels in OSCC patients were associated with poor overall survival. Moreover, multivariate cox proportional hazard models revealed that cytoplasmic IGF2BP2 expression, T status, and lymph node metastasis were independent prognostic factors for survival. In conclusion, IGF2BP2 protein was found to be a helpful predictive marker for OSCC patients, as well as a possible therapeutic target for OSCC treatment.
... The matrix metalloproteinases (MMPs) are a zinc-dependent endopeptidases family which is involved in extracellular matrix (ECM) degradation and tissue remodeling [18][19][20][21]. MMP-11, or stromelysin 3, is a proteolytic enzyme which belongs to the MMP family [22][23][24]. ...
Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide and the most prevalent cancer in Taiwan. The matrix metalloproteinase (MMP)-11 is a proteolytic enzyme of the MMP family which is involved in extracellular matrix degradation and tissue remodeling. In this study, we focused on the associations of MMP-11 single-nucleotide polymorphisms (SNPs) with CRC susceptibility and clinicopathological characteristics. The MMP-11 SNPs rs131451, rs738791, rs2267029, rs738792, and rs28382575 in 479 controls and 479 patients with CRC were analyzed with real-time polymerase chain reaction. We found that the MMP-11 SNP rs738792 “TC + CC” genotype was significantly associated with perineural invasion in colon cancer patients after controlling for clinical parameters [OR (95% CI) = 1.783 (1.074–2.960); p = 0.025]. The MMP-11 rs131451 “TC + CC” genotypic variants were correlated with greater tumor T status [OR (95% CI):1.254 (1.025–1.534); p = 0.028] and perineural invasion [OR (95% CI):1.773 (1.027–3.062); p = 0.040) in male CRC patients. Furthermore, analyses of The Cancer Genome Atlas (TCGA) revealed that MMP-11 levels were upregulated in colorectal carcinoma tissue compared with normal tissues and were correlated with advanced stage, larger tumor sizes, and lymph node metastasis. Moreover, the data from the Genotype-Tissue Expression (GTEx) database exhibited that the MMP-11 rs738792 “CC” and “CT” genotypic variants have higher MMP-11 expression than the “TT” genotype. In conclusion, our results have demonstrated that the MMP-11 SNPs rs738792 and rs131451 may have potential to provide biomarkers to evaluate CRC disease progression, and the MMP-11 rs131451 polymorphism may shed light on sex discrepancy in CRC development and prognosis.
... MMPs are involved in cell growth, invasion, survival, and adhesion in biological and pathological conditions, and then their activation Ivyspring International Publisher can cause cell proliferation, invasion and metastasis of cancer cells [4][5][6]. Tissue inhibitors of MMPs (TIMPs) are endogenous inhibitors of MMPs, and imbalance between the activities of MMPs and TIMPs may have an impact on cancer progression [7][8][9][10]. The TIMPs are known as a family of at least four 20 to 29 kDa proteins (TIMPs 1-4) which reversibly inhibit the MMPs [11]. ...
Single nucleotide polymorphisms (SNPs) of tissue inhibitor of metalloproteinases-3 (TIMP-3) have been revealed to be related to various cancers. To date, no study explores the relationships between TIMP-3 polymorphisms and uterine cervical cancer. The purposes of this research were to investigate the associations among genetic variants of TIMP-3 and development and clinicopathological factors of uterine cervical cancer, and patient 5 years survival in Taiwanese women. The study included 123 patients with invasive cancer and 97 with precancerous lesions of uterine cervix, and 300 control women. TIMP-3 polymorphisms rs9619311, rs9862 and rs11547635 were checked and their genotypic distributions were determined by real-time polymerase chain reaction. It showed that women with genotypes CT/TT in rs9862 were found to display a higher risk of developing cervical cancer with moderate and poor cell differentiation. Moreover, it revealed that cervical cancer patients carrying genotypes CC in rs9619311 exhibited a poorer 5 years survival, as compared to those with TT/TC in Taiwanese women, using univariate analysis. In addition, pelvic lymph node metastasis was determined to independently predict 5 years survival in cervical cancer patients using multivariate analysis. Conclusively, TIMP-3 SNPs polymorphisms rs9619311 are related to cervical patient survival in Taiwanese women.
... Also, the role of the thyroid hormones in promoting the metastatic process has been recently described [225] . Other hormones, like melatonin, for example, may inhibit cancer metastasis [226] . Patient with cancer have poor sleep and this may influence melatonin secretion. ...
Cancer is not just a lump of cells that divide, invade, and spread randomly, but rather a multi-layered precisely tuned process that requires the participation of the whole organism. There is an urgent need to zoom-out from the cellular and the local stromal view and broaden our perspective by including the whole organism level. Geographically separated cancer tissues communicate between themselves, forming a system that interacts with the rest of the organism through cancer induced systemic pathogenic networks. In the present paper, I introduce six systemic hallmarks of cancer that emerge as a result of these interactions. I also describe several potential therapeutic approaches that can be developed using the cancer system concept. Overall, I argue that the tumoricentric paradigm should be replaced with a broader approach that brings into focus the “cancerized” organism.
... 101 Melatonin significantly reduces alanine aminotransferase amounts, aspartate aminotransferase, cytokine secretions, and improves arsenic-induced liver damage in experimental models. 102 It overcomes apoptosis resistance in hepatocarcinoma and inhibits its progression. It stimulates Bcl-2, and downregulates Bax, caspase-3, and Cyt-C in tumor cytosol, thereby suppressing tumorigenesis. ...
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.
... In addition, cancer cells have several unique characteristics that give resistance to the human immune system and cancer treatment. As a result, cancer treatment remains associated with several challenges [1,2]. ...
Cancer is one of the diseases with the highest mortality rate today, with breast cancer being the second most common type among the Brazilian population. Due to its etiological complexity and inefficiency of treatments, studies have focused on new forms of treatment. Among these forms of treatment, hormonal therapy seems to be an excellent auxiliary mechanism in tumoricidal activity, and melatonin has great potential as a modulator of the immune system. Thus, the present study is aimed at evaluating the effect of the hormone melatonin on the coculture of colostrum polymorphonuclear cells and MCF-7 cancer cells and evaluates the effect of this hormone using a modified transport system. A feasibility analysis was performed by fluorescence microscopy at three cell incubation times, 2 hours, 24 hours, and 72 hours. The measurement of cytokines in the cell supernatant occurred in 24 hours, and the apoptosis assay was performed in 72 hours using flow cytometry. The results showed higher levels of cell viability in groups treated with melatonin and less viability in groups containing a coculture of polymorphonuclear cells and MCF-7 after 72 hours of incubation. Furthermore, the apoptosis and necrosis rates were higher in coculture polymorphonuclear and MCF-7 cells, especially in groups containing microemulsion as a modified release agent. These data suggest that melatonin, especially if associated with a modified release system, has immunomodulatory effects on human colostrum polymorphonuclear cells. These cells can play a crucial role in the resolution of the tumor through their mediation and inflammatory action.
... These studies have shown that melatonin improves the sensitivity of cancers to chemotherapy and has the potential to reverse drug resistance in tumors (Uguz et al., 2012;Dauchy et al., 2014;Xiang et al., 2015). Moreover, melatonin has been shown to inhibit molecular processes associated with metastasis (Su et al., 2017). Prior to cancer initiation, melatonin also serves as a free radical scavenger (Tan et al., 2002), preventing DNA damage that could lead to oncogenic mutations. ...
Sleep is a nearly ubiquitous phenomenon across the phylogenetic tree, highlighting its essential role in ensuring fitness across evolutionary time. Consequently, chronic disruption of the duration, timing, or structure of sleep can cause widespread problems in multiple physiological systems, including those that regulate energy balance, immune function, and cognitive capacity, among others. Many, if not all these systems, become altered throughout the course of cancer initiation, growth, metastatic spread, treatment, and recurrence. Recent work has demonstrated how changes in sleep influence the development of chronic diseases, including cancer, in both humans and animal models. A common finding is that for some cancers (e.g., breast), chronic disruption of sleep/wake states prior to disease onset is associated with an increased risk for cancer development. Additionally, sleep disruption after cancer initiation is often associated with worse outcomes. Recently, evidence suggesting that cancer itself can affect neuronal circuits controlling sleep and wakefulness has accumulated. Patients with cancer often report difficulty falling asleep, difficulty staying asleep, and severe fatigue, during and even years after treatment. In addition to the psychological stress associated with cancer, cancer itself may alter sleep homeostasis through changes to host physiology and via currently undefined mechanisms. Moreover, cancer treatments (e.g., chemotherapy, radiation, hormonal, and surgical) may further worsen sleep problems through complex biological processes yet to be fully understood. This results in a “chicken or the egg” phenomenon, where it is unclear whether sleep disruption promotes cancer or cancer reciprocally disrupts sleep. This review will discuss existing evidence for both hypotheses and present a framework through which the interactions between sleep and cancer can be dissociated and causally investigated.
... The devastating impact of shift work has increased research interest in sleep biomarkers, particularly melatonin, which is considered the 'gatekeeper' of circadian clocks (Söylemez, Sivri, Şimşek, Polat, & Çakır, 2014). Melatonin is secreted naturally by the pineal gland and is a key driver of the biological rhythm, which increases at night/during darkness hours and decreases in the early morning hours to prepare the body for wakefulness (Su et al., 2017). The immunomodulatory, anti-inflammatory, antioxidant, anti-ageing and vasoregulation functions of melatonin have been established (Talib, 2018). ...
... This is achieved by promoting DNA repair through activating related antioxidant pathways [62,92]. Night shift work-related circadian rhythm disruption reduces the secretion of melatonin, thus weakening the ability to repair DNA, leading to more susceptible cells being vulnerable to be affected by external carcinogens [93,94]. As for molecular level, melatonin can resynchronize the rhythm pattern of gene expression, correct the defects of various circadian genes responsible for cancer development in the expression pattern [95,96], and inhibit tumor signal transduction as well as the metabolic activity of cancer cells [97,98]. ...
The purpose of this study was to investigate the relationship between night shift work and breast cancer (BC) incidence. A search was performed in PubMed, EBSCO, Web of Science, and Cochrane Library databases before June 2021. The exposure factor of this study is night shift work, the primary outcome is the risk of BC. A total of 33 observational studies composed of 4,331,782 participants were included. Night shift work increases the risk of BC in the female population (hazard ratio [HR] = 1.20, 95% confidence interval [Cl] = 1.10–1.31, p < 0.001), especially receptor-positive BC, including estrogen receptor (ER)+ BC (HR = 1.35, p < 0.001), progesterone receptor (PR)+ BC (HR = 1.30, p = 0.003), and human epidermal growth factor receptor 2 (HER2)+ BC (HR = 1.42, p < 0.001), but has no effect on HER2− BC (HR = 1.10, p = 0.515) and ER−/PR− BC (HR = 0.98, p = 0.827). The risk of BC was positively correlated with night shift working duration, frequency, and cumulative times. For women who start night work before menopause, night work will increase the incidence of BC (HR = 1.17, p = 0.020), but for women who start night work after menopause, night work does not affect BC (HR = 1.04, p = 0.293). Night work can increase the incidence of BC in the female population. The effect of long working hours, frequency, and the cumulative number of night shifts on BC is influenced by menopausal status.
... [8][9][10][11] Accumulating evidence has indicated that melatonin exerts anti-tumor effects in multiple malignancies by inhibiting proliferation, angiogenesis and metastasis of tumor cells, and regulating tumor immunity. [11][12][13][14] However, the effects of melatonin on immunoregulation in HNSCC and its underlying mechanisms still remain unclear. ...
Melatonin is an endogenous hormone with various biological functions and possesses anti-tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in HNSCC patients were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among HNSCC patients. Moreover, melatonin significantly suppressed programmed death-ligand 1 (PD-L1) expression and inhibited epithelial-mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and vivo. In SCC7/C3H syngeneic mouse models, anti-programmed death-1 (PD-1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti-tumor immunity by increasing CD8+ T cell infiltration and decreasing regulatory T cell (Treg) proportion in tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD-L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti-PD-1 antibody in vivo, which could provide promising strategies for HNSCC treatment.
... MMPs [23,24]. Melatonin is also known to inhibit MMP-9 activity by directly interacting to its active site cleft [25]. ...
Aim
This study investigated the link between forced swim induced acute gastric ulceration, inflammation and MMP-3 along with the possible mechanism of protective efficacy of melatonin.
Main methods
We distributed Balb/c mice into four different groups. Group 1 and 2 were given PBS gavage. Group 3 and 4 were given melatonin (60 mg/kg b.wt.) and omeprazole (25 mg/kg b.wt.), respectively, an hour prior to forced swim. Ulcer index, tissue histology, immunohistochemistry, protein carbonylation, lipid peroxidation, Myeloperoxidase, Zymography, Western blotting, reactive oxygen species (ROS), mitochondrial dehydrogenase, mitochondrial transmembrane potential and bioinformatical analysis were performed.
Key findings
Our data revealed that gastric ulceration due to forced swim stress is responsible for overproduction of ROS, which may be a prime reason for mitochondrial dysfunction and induction of apoptosis via activation of Caspase-3. ROS is also responsible for p38 phosphorylation which in turn increases the activity of MMP-3 in ulcerated milieu, along with the oxidation of proteins, peroxidation of lipids and altered expression patterns of heat shock protein (HSP)-70. Melatonin is shown to reduce the inflammatory burden in gastric milieu and offers gastroprotection by binding to the active site of MMP-3; thereby inhibiting its activity, as suggested by in silico studies. Melatonin also inhibits the downregulation of HSP-70 and activates p38 dephosphorylation and thereby, it rescues gastric mucosal cells from stress-induced ulceration.
Significance
Our findings suggest that, melatonin imparts its gastroprotective effect by down-regulating the activation of MAPK-ERK pathway along with binding to the active site of MMP-3.
... 13,14 Melatonin has antitumor activity in different cancer types 15,16 and the capacity to reduce cancer cell motility and metastasis in several different tumors. 17,18 We have previously found that melatonin exhibits antimetastatic activity in osteolytic prostate cancer cells (PC3 and DU145 cell lines) by inhibiting matrix metalloproteinase (MMP)-13 production. 19 Importantly, melatonin inhibits osteoclastogenesis and suppresses prostate cancersecreted RANKL production, indicating its therapeutic potential for osteolytic prostate cancer bone metastases. ...
Advanced prostate cancer often develops into bone metastasis, which is characterized by aberrant bone formation with chronic pain and lower chances of survival. No treatment exists as yet for osteoblastic bone metastasis in prostate cancer. The indolamine melatonin (N-acetyl-5-methoxytryptamine) is a major regulator of the circadian rhythm. Melatonin has shown antiproliferative and antimetastatic activities, but has not yet been shown to be active in osteoblastic bone lesions of prostate cancer. Our study investigations reveal that melatonin concentration-dependently decreases the migratory and invasive abilities of two osteoblastic prostate cancer cell lines by inhibiting FAK, c-Src and NF-κB transcriptional activity via the melatonin MT1 receptor, which effectively inhibits integrin α2 β1 expression. Melatonin therapy appears to offer therapeutic possibilities for reducing osteoblastic bone lesions in prostate cancer. This article is protected by copyright. All rights reserved.
... The study of melatonin as an anti-cancer adjuvant [97][98][99] and oncostatic agent capable of inhibiting cancer metastasis while enhancing drug efficacy has been extensively documented and reviewed [100][101][102][103][104][105][106][107][108][109][110][111][112]. However, the interactions between melatonin and prions in cancer are not straightforward. ...
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
... Furthermore, research on MT has revealed a potential anti-cancer activity of MT in a variety of cancers, including prostate, breast, lung, liver, colon, etc. (8)(9)(10)(11)(12)(13)(14). The oncostatic actions of MT include induction of apoptosis, anti-proliferation, suppression of invasion and metastasis, anti-angiogenesis, and direct augmentation of immunomodulation (15). For example, in the literature, acting through its receptors MT1, MT inhibits PLC/p38c-Jun signaling pathway to repress expression of MMP13 and prostate carcinoma cells proliferation, migration and invasiveness (16). ...
Background:
Melatonin is a hormone naturally produced by the pineal gland in the brain. In addition to modulating circadian rhythms, it has pleiotropic biological effects including antioxidant, immunomodulatory, and anti-cancer effects. Herein, we report that melatonin has the ability to decrease the growth and metastasis of androgen-dependent prostate cancer.
Methods:
To evaluate the anti-cancer effect of melatonin on androgen-sensitive prostate cancer in vitro or in vivo, the effects of cell proliferation, apoptosis, migration and invasion were analyzed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell assay, and immunohistochemistry (IHC), respectively. Next, the interaction between androgen receptor (AR) and SUMO specific protease 1 (SENP1) was detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting, and confirmed by luciferase reporter assay. Furthermore, the Small Ubiquitin-like Modifier (SUMO) proteins are a group of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. (SUMOylation) of histone deacetylases 1 (HDAC1) was measured by proximity ligation assay (PLA).
Results:
The treatment of melatonin cripples the transcriptional activity of AR, which is essential for the growth of the androgen-dependent prostate cancer cell, LNCaP. The lower activity of AR was dependent on melatonin induced SUMOylation of HDAC1, which has been established as a key factor for the transcriptional activity of AR. Mechanistically, the effect of melatonin on AR was due to the decreased SENP1 protein level and the subsequent increased HDAC1 SUMOylation level. The overexpression of SENP1 abrogated the anti-cancer ability of melatonin on LNCaP cells.
Conclusions:
These findings indicate that melatonin is a suppressor of androgen-dependent prostate cancer tumorigenesis.
... Concerning cancer, melatonin as an anti-cancer agent is actively studied, which may involve biochemical and molecular mechanisms, [63] including inhibition mechanisms of cancer metastasis [64]. Specifically, melatonin may alter the adhesion and gap junctional intracellular communication or induce apoptotic cell death [63]. ...
Various melatonin supplementations have been developed to improve health outcomes in various clinical conditions. Thus, we sought to evaluate and summarize the effect of melatonin treatments in clinical settings for health outcomes. We searched PubMed/Medline, Embase, and Cochrane Library from inception to 4 February 2021. We included meta-analyses of randomized controlled trials investigating the melatonin intervention for any health outcome. Based on the different effect sizes of each meta-analysis, we calculated random models' standardized mean differences or risk ratios. We observed robust evidence supported by statistical significance with non-considerable heterogeneity between studies for sleep-related problems, cancer, surgical patients, and pregnant women. Patients with sleep disorder, sleep onset latency (SMD 0.33, 95% CI: 0.10 – 0.56, P < 0.01) were significantly improved whereas no clear evidence was shown with sleep efficiency (1.10, 95% CI: -0.26 – 2.45). The first analgesic requirement time (SMD 5.81, 95% CI: 2.57 - 9.05, P < 0.001) of surgical patients was distinctly improved. Female patients under artificial reproductive technologies had significant increase in the top-quality embryos (SMD 0.53, 95% CI: 0.27 – 0.79, P < 0.001), but no statistically clear evidence was found in the live birth rate (SMD 1.20, 95% CI: 0.83 – 1.72). Survival at one year (RR 1.90, 95% CI: 1.28 – 2.83, P < 0.005) significantly increased with cancer patients. Research on melatonin interventions to treat clinical symptoms and sleep problems among diverse health conditions was identified and provided considerable evidence. Future well-designed randomized clinical trials of high quality and subgroup quantitative analyses are essential.
... In cancer cells, the actions of melatonin in terms of oxidative stress are significantly more complex, as it can function as either an antioxidant or as a pro-oxidant [71]. All aspects of oncogenesis, i.e., initiation, tumor cell survival and dissemination [72][73][74][75], are influenced by the degree of reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. Free radical-mediated oxidative stress, together with apoptosis, is often activated in tumor cells by melatonin [76]. ...
Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which py-ruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production since acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic gly-colysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.
Background: Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer.
Methods : A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory & Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study.
Results : The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group.
Conclusions : The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer.
Combined chemotherapy is a treatment method based on the simultaneous use of two or more therapeutic agents; it is frequently necessary to produce a more effective treatment for cancer patients. Such combined treatments often improve the outcomes over that of the monotherapy approach, as the drugs synergistically target critical cell signaling pathways or work independently at different oncostatic sites. A better prognosis has been reported in patients treated with combination therapy than in patients treated with single drug chemotherapy. In recent decades, 5-fluorouracil (5-FU) has become one of the most widely used chemotherapy agents in cancer treatment. This medication, which is soluble in water, is used as the first line of anti-neoplastic agent in the treatment of several cancer types including breast, head and neck, stomach and colon cancer. Within the last three decades, many studies have investigated melatonin as an anti-cancer agent; this molecule exhibits various functions in controlling the behavior of cancer cells, such as inhibiting cell growth, inducing apoptosis, and inhibiting invasion. The aim of this review is to comprehensively evaluate the role of melatonin as a complementary agent with 5-FU-based chemotherapy for cancers. Additionally, we identify the potential common signaling pathways by which melatonin and 5-FU interact to enhance the efficacy of the combined therapy.
Graphic abstract
Hepatocellular carcinoma (HCC) is the major life-threatening primary liver malignancy in both sexes all over the world. Unfortunately, the majority of patients are diagnosed at later stages because HCC does not elicit obvious symptoms during its early incidence. Consequently, most individuals escape the first-line HCC treatments and are treated with chemotherapy. Regrettably, the therapeutic outcomes for those patients are usually poor because of the development of multidrug resistance phenomena. Furthermore, most anti-HCC therapies cause severe undesired side effects that notably interfere with the life quality of such patients. Accordingly, there is an important need to search for an alternative therapeutic drug or adjuvant which is more efficient with safe or even minimal side effects for HCC treatment. Melatonin was recently reported to exert intrinsic antitumor activity in different cancers. However, the regulatory pathways underlying the antitumor activity of melatonin are poorly understood in resistant liver cells. Furthermore, a limited number of studies have addressed the therapeutic role of melatonin in HCC cells resistant to doxorubicin chemotherapy. In this study, we investigated the antitumor effects of melatonin in doxorubicin-resistant HepG2 cells and explored the regulatory pivotal targets underlying these effects. To achieve our aim, an MTT assay was used to calculate the 50% inhibitory concentration of melatonin and evaluate its antiproliferative effect on resistant cells. Additionally, qRT-PCR was used to quantify genes having a role in drug resistance phenotype (ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2); apoptosis (caspases-3, and -7, Bcl2, Bax, and p53); anti-oxidation (NRF2); expression of melatonin receptors (MT1, MT2, and MT3); besides, programmed death receptor PD-1 gene. The active form of the caspase-3 enzyme was estimated by ELISA. A human inflammatory antibody membrane array was employed to quantify forty inflammatory factors expressed in treated cells. We observed that melatonin inhibited the proliferation of doxorubicin-resistant HepG2 cells in a dose-dependent manner after 24-h incubation time with a calculated IC50 greater than 10 mM (13.4 mM), the expression levels of genes involved in drug resistance response (ABCB1, ABCC1, ABCC5, and ABCG2) were downregulated. Also, the expression of caspase-3, Caspase-7, NRF2, and p53 genes were expressed at higher levels as compared to control (DMSO-treated cells). An active form of caspase-3 was confirmed by ELISA. Moreover, the anti-inflammatory effect of melatonin was detected through the calculated fold change to control which was reduced for various mediators that have a role in the inflammation pathway. The current findings introduce melatonin as a promising anti-cancer treatment for human-resistant HCC which could be used in combination with current chemotherapeutic regimens to improve the outcome and reduce the developed multidrug resistance.
Osteosarcoma (osteogenic sarcoma), the most prevalent primary malignant bone tumor in adolescents, confers low survival rates in patients with metastatic disease. Dietary curcumin has a number of anticancer properties but has poor bioavailability. To improve the clinical applications of curcumin, several potential curcumin analogs and nanobased curcumin delivery systems have been developed. In this critical review, we address the biological and pharmacological characteristics of curcumin and its analogs, with an emphasis on strategies to improve the bioactivity and bioavailability of curcumin analogs that may increase their application in the treatment of potent human metastatic osteosarcoma. We highlight promising current multifunctional nanoformulations and three-dimensional printed scaffold systems utilized for the targeting and delivery of curcumin in human osteosarcoma cells. Our purpose is to drive further research on curcumin analogs and carriers to improve their bioavailability and anti-osteosarcoma bioactivity.
Teaser: Dietary curcumin has a number of anticancer properties but has poor bioavailability. To improve the clinical applications of curcumin, several potential curcumin analogs and nanobased curcumin delivery systems have been developed to remedy its shortcomings.
Triple-negative breast cancer (TNBC) is an aggressive cancer insensitive to hormonal and human epidermal growth factor receptor 2 (HER2)-targeted therapies and has a poor prognosis. Therefore, there is a need for the development of convenient anticancer strategies for the management of TNBC. In this paper, we evaluate the antitumoral potential of a platinum(II) complex coordinated with the ligand 2-(3,5-diphenylpyrazol-1-yl)-2-thiazoline (DPhPzTn), hereafter PtDPhPzTn, against the TNBC cell line MDA-MB-231, and compared its effect with both cisplatin and its less lipophilic counterpart PtPzTn, the latter containing the ligand 2-(pyrazol-1-yl)-2-thiazoline (PzTn). Then, the putative potentiating actions of melatonin, a naturally occurring antioxidant with renowned antitumor properties, on the tumor-killing ability of PtDPhPzTn were also checked in TNBC cells. Our results show that PtDPhPzTn presented enhanced cytotoxicity compared to both the classical drug cisplatin and PtPzTn. In addition, PtDPhPzTn was able to induce apoptosis, being more selective for MDA-MB-231 cells when compared to non-tumor breast epithelial MCF10A cells. Likewise, PtDPhPzTn produced moderate S phase arrest and greatly impaired the migration ability of MDA-MB-231 cells. Most importantly, the co-stimulation of TNBC cells with PtDPhPzTn and melatonin substantially enhanced apoptosis and markedly improved the anti-migratory action compared to PtDPhPzTn alone. Altogether, our findings provide evidence that PtDPhPzTn and melatonin could be potentially applied to breast cancer treatment as powerful synergistic agents.
Among pulmonary arterial hypertension (PAH) patients, right ventricular (RV) functioning has been considered a major determining factor for cardiac capacity and survival. However, despite the recognition of the clinical importance for preserving RV functioning, no effective treatments are currently available for RV failure. This study aims to suggest one such possible treatment, through investigating the cardio-protective capabilities of the anti-oxidant, melatonin (Mel), for treating adverse RV remodeling in PAH, along with its underlying mechanisms. Arginine vasopressin induced neonatal rat cardiomyocyte hypertrophy in vitro; in vivo, PAH was induced in rats through intraperitoneal monocrotaline (MCT) injections, and Mel was administered intraperitoneally 24 h prior to MCT. Mel reduced rat cardiomyocyte hypertrophy and mitochondrial oxidative stress in vitro by activating the Mst1-Nrf2 pathway, which were all reversed upon siRNA knockdown of Mst1. Likewise, in vivo, Mel pre-treatment significantly ameliorated MCT-induced deterioration in cardiac function, RV hypertrophy, fibrosis and dilation. These beneficial effects were also associated with Mst1-Nrf2 pathway up regulation and its associated reduction in oxidative stress, as evidenced by the decrease in RV malondialdehyde content. Notably, results from Mel treatment were similar, or even superior, to those obtained from N-acetyl cysteine (NAC), which has already been-confirmed as an anti-oxidative treatment for PAH. By contrast, co-treatment with the Mst1 inhibitor XMU-MP-1 reversed all of those Mel-associated beneficial effects. Our findings thus identified Mel as a potent cardio-protective agent against the onset of maladaptive RV remodeling, through enhancement of the anti-oxidative response via Mst1-Nrf2 pathway activation.
Metastasis-a process that involves the migration of cells from the primary site to distant organs-is the leading cause of cancer-associated death. Improved technology and in-depth research on tumors have furthered our understanding of the various mechanisms involved in tumor metastasis. Metastasis is initiated by cancer cells of a specific phenotype, which migrate with the assistance of extracellular components and metastatic traits conferred via epigenetic regulation while modifying their behavior in response to the complex and dynamic human internal environment. In this review, we have summarized the general steps involved in tumor metastasis and their characteristics, incorporating recent studies and topical issues, including epithelial-mesenchymal transition, cancer stem cells, neutrophil extracellular traps, pre-metastatic niche, extracellular vesicles, and dormancy. Several feasible treatment directions have also been summarized. In addition, the correlation between cancer metastasis and lifestyle factors, such as obesity and circadian rhythm, has been illustrated.
Melatonin is a hormone synthesized in the pineal gland and has widespread physiological and pharmacological functions. Moreover, it can activate protective receptor‐dependent processes. These processes can prevent tissue carcinogenesis and inhibit malignant tumor progression and metastasis. Therefore, we investigated the regulatory effects of melatonin on dysregulated circRNAs in human lung adenocarcinoma (LUAD) cells. In this research, we treated LUAD cells with melatonin and measured the expression of hsa_circ_0017109, miR‐135b‐3p, and TOX3 by qRT‐PCR. Colony formation and CCK‐8 assays were used to determine cell proliferation. The wound‐healing assay and Transwell experiment were carried out to evaluate the migration potential and invasive capacity of LUAD cells. Also, cell apoptosis was detected using a Cell Apoptosis Kit, and protein production was identified by Western blot. It was suggested that melatonin could inhibit LUAD progression in vivo and in vitro, and the role of TOX3 in this process was explored. Additionally, hsa_circ_0017109 was found to sponge miR‐135b‐3p, a downstream factor of circ_0017109, which was demonstrated to target TOX3 in LUAD cells could promote hippo pathway and epithelial‐mesenchymal transition (EMT) pathway. To summarize, we demonstrated that melatonin decreases the expression of circ_0017109 and suppresses NSCLC cell migration, invasion, and proliferation through decreasing TOX3 expression via direct activationof miR‐135b‐3p. This article is protected by copyright. All rights reserved.
Purpose:
Bladder cancer is a kind of common malignant cancer in the urinary system. The expression of EDARADD (ectodysplasin-A receptor-associated death domain) in bladder cancer is higher than the normal samples. However, its role in bladder cancer remains unknown. In the present study, we analyzed the expression of EDARADD in 81 bladder cancer samples by immunohistochemistry as well as its correlation with clinical characteristics. In addition, the role of EDARADD was also explored through loss of function.
Materials and methods:
Cell proliferation assay and MTT assay were conducted to assess the proliferation of bladder cancer cells and transwell assay and wound healing assay were conducted to assess the migration of bladder cancer cells. On the other hand, the levels of epithelial-mesenchymal transition (EMT) associated proteins and the key molecules in the MAPK signaling pathway were detected by western blot. In vivo experiments were also conducted to determine the effect of EDARADD silencing on the metastasis of bladder cancer cells and the MAPK signaling pathway.
Results:
EDARADD was highly expressed in bladder cancer samples, especially in high-grade bladder cancer samples. The high EDARADD level indicated a poor survival. Interestingly, EDARADD silencing suppressed the proliferation, migration and EMT of bladder cancer cells. Furthermore, the MAPK signaling pathway was repressed by EDARADD silencing. Additionally, silencing EDARADD also inhibited the metastasis of bladder cancer and the MAPK signaling pathway in vivo. It is indicated that silencing EDARADD may suppress the proliferation and metastasis of bladder cancer cells through the MAPK signaling pathway.
Conclusion:
These results indicate that EDARADD may become a probable target for the treatment of bladder cancer.
Hematological malignancies including leukemia, multiple myeloma and lymphoma are known as leading causes of death around the world. Despite all developments in cancer management, current therapeutic methods are still relatively inefficient, leading to the heavy financial burdens for public health systems. Strategic attempts in clinical practice must be based on three serious goals including: 1) increasing the efficacy of treatments and decreasing their side‐effects, 2) decreasing financial price of treatments and related morbidity and mortality rates, and 3) improving life quality and survival of affected patients. Melatonin, a multipotential neurohormone mainly secreted by the pineal gland, has recently been shown to play essential roles in the treatment of various human diseases. Moreover, it possesses anticancer impacts and acts through regulation of underlying cellular and molecular mechanisms. In this article, we review mechanistic roles and beneficial effects of melatonin against hematological cancers, especially lymphoma.
Nasopharyngeal carcinoma (NPC) is endemic in Southeast Asia and the main cause of treatment failure is metastasis. A lot of biological and pharmacological actions of dihydromyricetin (DHM) have been reported such as regulating glucose and anti‐cancer effects. The effects of DHM on the cancer invasion and migration of NPC, however, are still unclear. We therefore investigated the in vitro anti‐metastatic properties of DHM on three human NPC cell lines (HONE‐1, NPC‐39, and NPC‐BM), as well as the underlying signaling pathways. Our study revealed that DHM could suppress the migration and invasion in NPC cells. Gelatin zymography assay and western blotting assays demonstrated that DHM suppressed the enzyme activity and protein expression of matrix metalloproteinases‐2 (MMP‐2). Mitogen‐activated protein kinases were also investigated to elucidate the signaling pathway, which showed that phosphorylation of extracellular signal‐regulated kinase 1 and 2 (ERK1/2) was inhibited after the treatment of DHM. In conclusion, our data revealed that DHM inhibited the migration and invasion of NPC cells by suppressing the expression of MMP‐2 via down regulating the ERK1/2 signaling pathway.
Background
Colon cancer is one of the most important causes of death in the entire world. New pharmacological strategies are always needed, especially in resistant variants of this pathology. We have previously reported that drugs such as menadione (MEN), D, L-buthionine-S,R-sulfoximine or calcitriol, used in combination, enhanced cell sensibility of breast and colon tumour models, due to their ability to modify the oxidative status of the cells. Melatonin (MEL), a hormone regulating circadian rhythms, has anti-oxidant and anti-apoptotic properties at low concentrations, while at high doses, it has been shown to inhibit cancer cell growth.
Objective
The objective of this study is to determine the antitumoral action of the combination MEN and MEL on colon cancer cells.
Methods
Caco-2 cells were employed to evaluate the effects of both compounds, used alone or combined, on cellular growth/morphology, oxidative and nitrosative stress, and cell migration.
Results
MEN plus MEL dramatically reduced cell proliferation in a time and dose-dependent manner. The antiproliferative effects began at 48 h. At the same time, the combination modified the content of superoxide anion, induced the formation of reactive nitrogen species and enhanced catalase activity. Cell migration process was delayed. Also, changes in nuclear morphology consistent with cell death were observed. Conclusion: The enhanced effect of simultaneous use of MEN and MEL on Caco-2 cells suggests that this combined action may have therapeutic potential as an adjuvant on intestinal cancer acting in different oncogenic pathways.
Ethnopharmacological relevance
Uvangoletin is a dihydrochalcone extracted from the traditional Chinese medicinal plant Sarcandra glabra. Previous research has showed that uvangoletin could induce leukemia cell death. However, the anticancer effect of uvangoletin on hepatocellular carcinoma (HCC) has not been clarified.
Aim of the study
This study aimed to investigate the anti-cancer effects of uvangoletin on HCC and to explore its underlying mechanisms.
Materials and methods
We measured the anticancer activities of uvangoletin both in vitro and in vivo by MTT assay and HepG2 xenograft model. The effects of uvangoletin on apoptosis, autophagy, migration and invasion were also determined. Apoptosis was evaluated by flow cytometry method. Autophagy was assessed by immunofluorescence assay. Cell migration and invasion ability were validated by wound healing assay and cultrex® 96 well cell migration/invasion assay. The expression level of relevant proteins and pathways were examined by western blot.
Results
The results of MTT assay and HepG2 xenograft model showed that uvangoletin could inhibit HCC cells proliferation in vitro and in vivo. Uvangoletin could induce HepG2 cell apoptosis as evidence by the increased expression of cleaved caspase 3, caspase 8 and Bax while decreased Bcl-2 expression. Wound healing assay and transwell assay showed that uvangoletin inhibited HepG2 cells migration and invasion and reduced vimentin, MMP9, MMP2 expression. Uvangoletin also promoted autophagy in HepG2 cells as confirmed by the accumulation of GFP-LC3 puncta. Autophagy inhibitors like 3-MA or CQ could suppress uvangoletin-induced apoptosis. Importantly, uvangoletin-induced anti-EMT effect was also attenuated after autophagy inhibitors added in. Mechanistically, the expressions of p-JNK, p-ERK, p-p38, p-AKT, p-p70S6k and p-mTOR were significantly decreased after uvangoletin treatment.
Conclusion
Our results showed that uvangoletin could induce apoptotic and autophagic cell death, inhibit cell proliferation and metastasis on HepG2 cells through Akt/mTOR, MAPK and TGFβ/Smad2 signal pathways.
Atopic dermatitis (AD) is caused by multiple factors that trigger chronic skin inflammation, including a defective skin barrier, immune cell activation, and microbial exposure. Although melatonin has an excellent biosafety profile and a potential to treat AD, there is limited clinical evidence from controlled trials that support the use of melatonin as an AD treatment. The delivery of melatonin via the transdermal delivery system is also a challenge in designing melatonin-based AD treatments. In this study, we generated melatonin-loaded extracellular vesicle-mimetic nanoparticles (MelaNVs) to improve the transdermal delivery of melatonin and to evaluate their therapeutic potential in AD. The MelaNVs were spherical nanoparticles with an average size of 100 nm, which is the optimal size for the transdermal delivery of drugs. MelaNVs showed anti-inflammatory effects by suppressing the release of TNF-α and β-hexosaminidase in LPS-treated RAW264.7 cells and compound 48/80-treated RBL-2H3 cells, respectively. MelaNVs showed a superior suppressive effect compared to an equivalent concentration of free melatonin. Treating a 2,4-dinitrofluorobenzene (DNCB)-induced AD-like mouse model with MelaNVs improved AD by suppressing local inflammation, mast cell infiltration, and fibrosis. In addition, MelaNVs effectively suppressed serum IgE levels and regulated serum IFN-γ and IL-4 levels. Taken together, these results suggest that MelaNVs are novel and efficient transdermal delivery systems of melatonin and that MelaNVs can be used as a treatment to improve AD.
Nuclear orpan receptors are members of the superfamily of structurally related, ligand-inducible transcription factors for which no ligand has yet been identified. Over the past few years many nuclear orphan receptors have been cloned, but only for the retinoid X receptor (RXR) has a natural ligand (9-cis-retinoic acid) been found. Here we report the identification of melatonin as a ligand for the recently cloned orphan receptor retinoid Z receptor beta (RZR beta). We found RZR beta expression in the rat brain nearly coincident with binding sites for the pineal gland hormone melatonin (5-methoxy-N-acetyltryptamine). We show here binding and activation of RZR beta by melatonin with Kd and EC50 values in the low nanomolar range. A nuclear signaling pathway for melatonin may contribute to some of the diverse and profound effects of this hormone, for example, in the context of circadian rhythmicity.
Nasopharyngeal carcinoma (NPC), a disease common in the South-East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, fungi, and bacteria, has oncotstatic activity via several mechanisms. The molecular mechanisms involved in melatonin-mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA-induced cell motility by regulating matrix metalloproteinase-9 (MMP-9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP-9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein-1 (SP-1)-DNA. Our mechanistic analysis further reveals that the c-Jun N terminal kinase/mitogen-activate protein kinase pathway is involved in the melatonin-mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin-mediated MMP-9 regulation and tumor suppressing ability and provide new insights into the role of melatonin-induced molecular and epigenetic regulation of tumor growth. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA-induced MMP-9 gene expression via inhibiting SP-1-DNA binding ability. The results provide a functional link between melatonin-mediated SP-1 regulation and the anti-metastatic actions of melatonin on nasopharyngeal carcinoma. This article is protected by copyright. All rights reserved.
Cancer stem cells (CSCs) pose a challenge in cancer treatment, as these cells can drive tumor growth and are resistant to chemotherapy. Melatonin exerts its oncostatic effects through the estrogen receptor (ER) pathway in cancer cells, however its action in CSCs is unclear. Here, we evaluated the effect of melatonin on the regulation of the transcription factor OCT4 (Octamer Binding 4) by estrogen receptor alpha (ERα) in breast cancer stem cells (BCSCs). The cells were grown as a cell suspension or as anchorage independent growth, for the mammospheres growth, representing the CSCs population and treated with 10 nM estrogen (E2) or 10 μM of the environmental estrogen Bisphenol A (BPA) and 1 mM of melatonin. At the end, the cell growth as well as OCT4 and ERα expression and the binding activity of ERα to the OCT4 was assessed. The increase in number and size of mammospheres induced by E2 or BPA was reduced by melatonin treatment. Furthermore, binding of the ERα to OCT4 was reduced, accompanied by a reduction of OCT4 and ERα expression. Thus, melatonin treatment is effective against proliferation of BCSCs in vitro and impacts the ER pathway, demonstrating its potential therapeutic use in breast cancer.
The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the antimetastatic actions of melatonin have not been well established. In the present study, the antimetastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition, and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer.
Implications:
Melatonin inhibition of Rsk2 represses the metastatic phenotype in breast cancer cells suppressing EMT or inhibiting other mechanisms that promote metastasis; disruption of the melatonin signal may promote metastatic progression in breast cancer. Mol Cancer Res; 14(11); 1159-69. ©2016 AACR.
Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its anti-radical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely-diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule. This article is protected by copyright. All rights reserved.
Elevated heart rate is a risk factor for cardiovascular and all-cause mortalities in the general population and various cardiovascular pathologies. Insufficient heart rate decline during the night, that is, nondipping heart rate, also increases cardiovascular risk. Abnormal heart rate reflects an autonomic nervous system imbalance in terms of relative dominance of sympathetic tone. There are only a few prospective studies concerning the effect of heart rate reduction in coronary heart disease and heart failure. In hypertensive patients, retrospective analyses show no additional benefit of slowing down the heart rate by beta-blockade to blood pressure reduction. Melatonin, a secretory product of the pineal gland, has several attributes, which predict melatonin to be a promising candidate in the struggle against elevated heart rate and its consequences in the hypertensive population. First, melatonin production depends on the sympathetic stimulation of the pineal gland. On the other hand, melatonin inhibits the sympathetic system in several ways representing potentially the counter-regulatory mechanism to normalize excessive sympathetic drive. Second, administration of melatonin reduces heart rate in animals and humans. Third, the chronobiological action of melatonin may normalize the insufficient nocturnal decline of heart rate. Moreover, melatonin reduces the development of endothelial dysfunction and atherosclerosis, which are considered a crucial pathophysiological disorder of increased heart rate and pulsatile blood flow. The antihypertensive and antiremodeling action of melatonin along with its beneficial effects on lipid profile and insulin resistance may be of additional benefit. A clinical trial investigating melatonin actions in hypertensive patients with increased heart rate is warranted. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Non-small-cell lung cancer (NSCLC) is a leading cause of death from cancer worldwide. Melatonin, an idoleamine discovered in the pineal gland, exerts pleiotropic anticancer effects against a variety of cancer types. In particular, melatonin may be an important anticancer drug in the treatment of NSCLC. Herein, we review the correlation between the disruption of the melatonin rhythm and NSCLC incidence; we also evaluate the evidence related to the effects of melatonin in inhibiting lung carcinogenesis. Special focus is placed on the oncostatic effects of melatonin, including anti-proliferation, induction of apoptosis, inhibition of invasion and metastasis, and enhancement of immunomodulation. We suggest the drug synergy of melatonin with radio- or chemotherapy for NSCLC could prove to be useful. Taken together, the information complied herein may serve as a comprehensive reference for the anticancer mechanisms of melatonin against NSCLC, and may be helpful for the design of future experimental research and for advancing melatonin as a therapeutic agent for NSCLC.
Melatonin exerts antimetastatic effects on liver and breast cancer and also inhibits matrix metalloproteinase (MMP) activity. However, the detailed impacts and underlying mechanisms of melatonin on oral cancer cell metastasis are still unclear. This study showed that melatonin attenuated the 12-O-tetradecanoylphorbol-13-acetate-induced migration of oral cancer cell lines, HSC-3 and OECM-1. Zymography, quantitative real-time PCR, and Western blotting analyses revealed that melatonin lessened MMP-9 enzyme activity as well as the expression of MMP-9 mRNA and protein. Furthermore, melatonin suppressed the phosphorylation of the ERK1/2 signalling pathway, which dampened MMP-9 gene transcription by affecting the expression of transcriptional coactivators, such as CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300), and decreasing histone acetylation in HSC-3 and OECM-1 cells. Examinations on clinical samples exhibited that MMP-9, CREBBP, and EP300 were significantly increased in oral cancer tissues. Moreover, the relative level of CREBBP was positively correlated with the expression of MMP-9 and EP300. In conclusion, we demonstrated that melatonin inhibits the motility of HSC-3 and OECM-1 cells in vitro through a molecular mechanism that involves attenuation of MMP-9 expression and activity mediated by decreased histone acetylation.
Cancer stem cells (CSCs) have been associated with metastasis and therapeutic resistance and can be generated via epithelial mesenchymal transition (EMT). Some studies suggest that the hormone melatonin acts in CSCs and may participate in the inhibition of the EMT. The objectives of this study were to evaluate the formation of mammospheres from the canine and human breast cancer cell lines, CMT-U229 and MCF-7, and the effects of melatonin treatment on the modulation of stem cell and EMT molecular markers: OCT4, E-cadherin, N-cadherin and vimentin, as well as on cell viability and invasiveness of the cells from mammospheres. The CMT-U229 and MCF-7 cell lines were subjected to three-dimensional culture in special medium for stem cells. The phenotype of mammospheres was first evaluated by flow cytometry (CD44+/CD24low/- marking). Cell viability was measured by MTT colorimetric assay and the expression of the proteins OCT4, E-cadherin, N-cadherin and vimentin was evaluated by immunofluorescence and quantified by optical densitometry. The analysis of cell migration and invasion was performed in Boyden Chamber. Flow cytometry proved the stem cell phenotype with CD44+/CD24low/- positive marking for both cell lines. Cell viability of CMT-U229 and MCF-7 cells was reduced after treatment with 1mM melatonin for 24 h (P<0.05). Immunofluorescence staining showed increased E-cadherin expression (P<0.05) and decreased expression of OCT4, N-cadherin and vimentin (P<0.05) in both cell lines after treatment with 1 mM melatonin for 24 hours. Moreover, treatment with melatonin was able to reduce cell migration and invasion in both cell lines when compared to control group (P<0.05). Our results demonstrate that melatonin shows an inhibitory role in the viability and invasiveness of breast cancer mammospheres as well as in modulating the expression of proteins related to EMT in breast CSCs, suggesting its potential anti-metastatic role in canine and human breast cancer cell lines.
Rho-associated coiled-coil kinase (ROCK) is a major downstream effector of the small GTPase RhoA. The ROCK family, consisting of ROCK1 and ROCK2, plays a central role in the organization of the actin cytoskeleton, and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Since the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored in numerous diseases, including cancer. Accumulating evidence supports the concept that ROCK plays important roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance as well. This review focuses on the new advances of the most recent 5 years from the studies on the roles of ROCK in cancer development and progression; the discussion is mainly focused on the potential value of ROCK inhibitors in cancer therapy.
Metastasis is the primary cause of mortality for cancer patients. Understanding the molecular and cellular mechanisms that underlie metastatic spread is critical for the development of effective therapeutic approaches. Acquisition of migratory and invasive properties by tumors cells is mediated by induction of Epithelial-Mesenchymal Transition (EMT). This program is orchestrated by a network of transcription factors including Twist1, Snai1/2, and Zeb1/2. Recent studies have demonstrated the requirement of a dynamic regulation of EMT during tumor progression to first promote tumor cell dissemination and then allow metastatic outgrowth. However, we currently lack a complete understanding of how this process is induced and then repressed during the metastasis cascade.1 Past studies largely have focused on biochemical signals that induce EMT including TGF-β, hypoxia, and inflammatory cytokines. Landmark studies identified a functional role for the mechanical forces generated by stiffening matrix during tumor progression in driving tumor malignancy.2,3 How such biomechanical cues are recognized and subsequently transduced into biochemical and transcriptional signals to modulate tumor cell behavior is unclear.
The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both in vivo and in vitro. These effects are mediated by two specific, high-affinity, seven trans-membrane, pertussis-toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-, α- as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies pin-pointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3 and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function lead to metabolic disturbances, for example type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both, type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased insulin levels, whereas type 1 diabetic rats show extremely reduced levels or the absence of insulin, but statistically significant increases in melatonin levels. Briefly, an increase in melatonin levels leads to a decrease in stimulated insulin secretion and vice versa. Melatonin levels in blood plasma, as well as the activity of the key enzyme of melatonin synthesis, AA-NAT (arylalkylamine-N-acetyltransferase) in pineal are lower in type 2 diabetic rats compared to controls. In contrast, melatonin and pineal AA-NAT mRNA are increased and insulin receptor mRNA is decreased in type 1 diabetic rats, which also indicates a close relationship between insulin and melatonin. As an explanation it was hypothesized that catecholamines, which reduce insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. This conviction stems from the observation that catecholamines are increased in type 1 but are diminished in type 2 diabetes. In this context another important line of inquiry involves the fact that melatonin protects β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
This review discusses recent work on melatonin-mediated circadian regulation and molecular and metabolic signaling mechanisms involved in human breast cancer growth and associated consequences of circadian disruption by exposure to light at night (LEN). Anti-proliferative effects of the circadian melatonin signal are, typically, mediated through mechanisms involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor alpha (ERα)-positive human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα. Melatonin also regulates the transcriptional activity of additional members of the nuclear receptor super-family, enzymes involved in estrogen metabolism, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (Warburg effect), and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways including inhibition of p38 MAPK and repression of epithelial-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in both rats and humans indicate that LEN induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, signaling, and drives breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest mechanistic support yet for epidemiological studies demonstrating the elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN.
Background: Melatonin, a well-known antioxidant, has been shown to possess anti-invasive properties for glioma. However, little is known about the effect of melatonin on glioma cell migration and invasion under hypoxia, which is a crucial microenvironment for tumor progress. In addition, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are closely associated with cell migration and invasion. Therefore, we investigated the possible role of these kinases and its related signaling in the regulation of human U251 glioma cells behavior by melatonin under hypoxia.
Methods: The abilities of migration and invasion of U251 glioma cells were determined by wound healing and transwell assay in vitro. The intracellular production of reactive oxygen species (ROS) was measured by using the fluorescent probe 6-carboxy-2′, 7′-dichorodihydrofluorescein diacetate (DCFH-DA). Immunofluorescence experiments and western blotting analysis were used to detect the expression level of protein. Small interfering RNAs (siRNA) was used to silence specific gene expression.
Results: The pharmacologic concentration (1 mM) of melatonin significantly inhibited the migration and invasion of human U251 glioma cells under hypoxia. The inhibitory effect of melatonin was accompanied with the reduced phosphorylation of FAK and Pyk2, and decreased expression of alpha v beta 3 (αvβ3) integrin. Additionally, inhibition of αvβ3 integrin by siRNA reduced the phosphorylation of FAK/Pyk2 and demonstrated the similar anti-tumor effects as melatonin, suggesting the involvement of αvβ3 integrin- FAK/Pyk2 pathway in the anti-migratory and anti-invasive effect of melatonin. It was also found that melatonin treatment decreased
the ROS levels in U251 glioma cells cultured under hypoxia. ROS inhibitor apocynin not only inhibited αvβ3 integrin expression and the phosphorylation levels of FAK and Pyk2, but also suppressed the migratory and invasive capacity of U251 glioma cells under hypoxia.
Conclusions: These results suggest that melatonin exerts anti-migratory and anti-invasive effects on glioma cells in response to hypoxia via ROS-αvβ3 integrin-FAK/Pyk2 signaling pathways. This provides evidence that melatonin may be a potential therapeutic molecule targeting the hypoxic microenvironment of glioma.
EMT and MET comprise the processes by which cells transit between epithelial and mesenchymal states, and they play integral roles in both normal development and cancer metastasis. This article reviews these processes and the molecular pathways that contribute to them. First, we compare embryogenesis and development with cancer metastasis. We then discuss the signaling pathways and the differential expression and down-regulation of receptors in both tumor cells and stromal cells, which play a role in EMT and metastasis. We further delve into the clinical implications of EMT and MET in several types of tumors, and lastly, we discuss the role of epigenetic events that regulate EMT/MET processes. We hypothesize that reversible epigenetic events regulate both EMT and MET, and thus, also regulate the development of different types of metastatic cancers.
The involvement of melatonin in mammalian brain pathophysiology has received growing interest, but information about the anatomical distribution of its two G-protein coupled receptors, MT1 and MT2 , remains elusive. In the present study, using specific antibodies, we examined the precise distribution of both melatonin receptors immunoreactivity across the adult rat brain using photon, confocal, and electron microscopy. Our results demonstrate a selective MT1 and MT2 localization on neuronal cell bodies and dendrites in numerous regions of the rat telencephalon, diencephalon and mesencephalon. Confocal and ultrastructural examination confirmed the somatodendritic nature of MT1 and MT2 receptors, both being localized on neuronal membranes. Overall, striking differences were observed in the anatomical distribution pattern of MT1 and MT2 proteins, and the labeling often appeared complementary in regions displaying both receptors. Somadendrites labeled for MT1 were observed for instance in the retrosplenial cortex, the dentate gyrus of the hippocampus, the islands of Calleja, the medial habenula, the suprachiasmatic nucleus, the superior colliculus, the substantia nigra pars compacta, the dorsal raphe nucleus, and the pars tuberalis of the pituitary gland. Somadendrites endowed with MT2 receptors were mostly observed in the CA3 field of the hippocampus, the reticular thalamic nucleus, the supraoptic nucleus, the inferior colliculus, the substantia nigra pars reticulata and the ventrolateral periaqueductal gray. Together, these data provide the first detailed neurocytological mapping of melatonin receptors in the adult rat brain, an essential prerequisite for a better understanding of melatonin distinct receptor function and neurophysiology. This article is protected by copyright. All rights reserved.
Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.
Background:
Oral cancer is the most common type of head and neck cancer and its high rate of mortality and morbidity is closely related to the processes of angiogenesis and tumor metastasis. The overexpression of the pro-angiogenic genes, HIF-1α and VEGF, and pro-metastatic gene, ROCK-1, are associated with unfavorable prognosis in oral carcinoma. Melatonin has oncostatic, antiangiogenic and antimetastatic properties in several types of neoplasms, although its relationship with oral cancer has been little explored. This study aims to analyze the expression of the genes HIF-1α, VEGF and ROCK-1 in cell lines of squamous cell carcinoma of the tongue, after treatment with melatonin.
Methods:
SCC9 and SCC25 cells were cultured and cell viability was assessed by MTT assay, after treatment with 100 μM of CoCl2 to induce hypoxia and with melatonin at different concentrations. The analysis of quantitative RT-PCR and the immunocytochemical analysis were performed to verify the action of melatonin under conditions of normoxia and hypoxia, on gene and protein expression of HIF-1α, VEGF and ROCK-1.
Results:
The MTT assay showed a decrease in cell viability in both cell lines, after the treatment with melatonin. The analysis of quantitative RT-PCR indicated an inhibition of the expression of the pro-angiogenic genes HIF-1α (P < 0.001) and VEGF (P < 0.001) under hypoxic conditions, and of the pro-metastatic gene ROCK-1 (P < 0.0001) in the cell line SCC9, after treatment with 1 mM of melatonin. In the immunocytochemical analysis, there was a positive correlation with gene expression data, validating the quantitative RT-PCR results for cell line SCC9. Treatment with melatonin did not demonstrate inhibition of the expression of genes HIF-1α, VEGF and ROCK-1 in line SCC25, which has different molecular characteristics and greater degree of malignancy when compared to the line SCC9.
Conclusion:
Melatonin affects cell viability in the SCC9 and SCC25 lines and inhibits the expression of the genes HIF-1α, VEGF and ROCK-1 in SCC9 line. Additional studies may confirm the potential therapeutic effect of melatonin in some subtypes of oral carcinoma.
Melatonin is a small, highly conserved indole with numerous receptor-mediated and receptor-independent actions. Receptor-dependent functions include circadian rhythm regulation, sleep, and cancer inhibition. The receptor-independent actions relate to melatonin's ability to function in the detoxification of free radicals, thereby protecting critical molecules from the destructive effects of oxidative stress under conditions of ischemia/reperfusion injury (stroke, heart attack), ionizing radiation, and drug toxicity, among others. Melatonin has numerous applications in physiology and medicine.
Objective
Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. But, the mechanisms for the anti-cancer effects are unknown. The present study explored the effects of melatonin on the migration of human lung adenocarcinoma A549 cells and its mechanism.
Methods
MTT assay was employed to measure the viability of A549 cells treated with different concentrations of melatonin. The effect of melatonin on the migration of A549 cells was analyzed by wound healing assay. Occludin location was observed by immunofluorescence. The expression of occludin, osteopontin (OPN), myosin light chain kinase (MLCK) and phosphorylation of myosin light chain (MLC), JNK were detected by western blots.
Results
After A549 cells were treated with melatonin, the viability and migration of the cells were inhibited significantly. The relative migration rate of A549 cells treated with melatonin was only about 20% at 24 h. The expression level of OPN, MLCK and phosphorylation of MLC of A549 cells were reduced, while the expression of occludin was conversely elevated, and occludin located on the cell surface was obviously increased. The phosphorylation status of JNK in A549 cells was also reduced when cells were treated by melatonin.
Conclusions
Melatonin significantly inhibits the migration of A549 cells, and this may be associated with the down-regulation of the expression of OPN, MLCK, phosphorylation of MLC, and up-regulation of the expression of occludin involving JNK/MAPK pathway.
Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.
Introduction:
Compelling evidence has highlighted the complex pleiotropic functions elicited by the melatonin in cancer cells. Melatonin behaves as a 'smart killer', i.e., modulating anti-apoptotic processes in normal cells, and triggering pro-apoptotic signals in cancer cells.
Areas covered:
Melatonin induces programmed cell death in a wide range of different tumors (breast, gastro-intestinal, hematological, prostate, osteosarcoma, melanoma, kidney, etc…). Mechanisms of action and molecular pathways involved in pro-apoptotic processes under melatonin treatment are discussed.
Expert opinion:
Melatonin involvement in apoptotic processes is a new and relevant field of investigation. Even in tumor models unresponsive to melatonin alone, this hormone can significantly amplify the cytostatic and the cytotoxic effects triggered by other compounds or conventional drugs. We are far from having a satisfactory understanding about how and when melatonin exerts its beneficial effects. Melatonin in the nanomolar range activates the intrinsic and/or the extrinsic apoptotic pathway in cancer cells, namely through an increase in the p53/MDM2p ratio and downregulation of Sirt1. This finding is of great relevance since there is intense research ongoing to identify nontoxic feasible inhibitors of MDM2 and Sirt1. Melatonin should be evaluated for the management of those cancers where both of these are overexpressed and functionally strategic.
