TY - JOUR
AU - Lupi, Luiz, Antonio
AB - Abstract Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers, and most patients develop chemoresistance after first-line treatments. Despite recent advances, the 5-year relative survival is ~45% for all OC subtypes, and invasive epithelial OC has only a 17% survival rate when diagnosed at a late stage. Identification of new efficacious molecules or biomarkers represents important opportunities in the treatment of OC. The pharmacological and physiological properties of melatonin indicate this agent could be useful against OC progression and metastasis. In normal cells, melatonin has potent antioxidant and anti-apoptotic actions. Conversely, melatonin has pro-oxidant as well as anti-proliferative, anti-angiogenic and immunomodulatory properties in many cancer types including hormone-dependent cancers. Although melatonin receptors have been identified in OC cells, the exact mechanism by which melatonin induces anticancer activities remains incompletely understood. Clinical studies have reported negative correlation between aggressiveness of OC and serum levels of melatonin, reinforcing the idea that melatonin may be a critical factor determining OC development. In vitro and in vivo studies suggest melatonin differentially regulates multiple signaling pathways in OC cells. This focused review explores the potential mechanisms of action of melatonin on cultured OC cells and in experimental models of OC in an attempt to clarify how melatonin modulates the signaling pathways involved in cancer cell apoptosis, survival, inflammation, proliferation and metabolic processes. Based on the evidence presented, we feel that melatonin, as an agent that controls cellular signals associated with malignancy, may be beneficial in combination with other therapeutics for OC treatment. Introduction A brief description of molecular aspects involving the anticancer properties of melatonin A variety of new agents has been proposed to counteract ovarian cancer (OC) as adjuvant therapeutic strategies, including melatonin. Melatonin (N-acetyl-5-methoxytryptamine) is a small lipophilic indoleamine produced by the pineal gland and by extrapineal tissues (e.g. ovary, retina, gastrointestinal tract). In healthy cells, melatonin prevents apoptosis through a variety of well-recognized mechanisms (1). On the contrary, it has been consistently reported to exert antiproliferative, anti-angiogenic, pro-apoptotic and immunomodulatory properties in many cancer types including OC (2). Molecular mechanisms by which melatonin exhibits its oncostatic action include the regulation of estrogen receptor expression, protein kinases activities, calcium/calmodulin signals, cellular redox state, cytoskeletal reorganization and function, melatonin receptor-mediated cell signaling, fatty acid metabolism and suppression/activation of the intracellular signal transduction (3). In addition, melatonin exerts anticancer effects through its anti-metastatic potential, drug sensitivity restoration, apoptosis induction, growth inhibition and anti-angiogenic and anti-invasive actions (4). Importantly, Reiter et al. (5) extensively summarized the literature showing that melatonin mitigates a number of cancer types at the initiation, progression and metastasis levels; the processes by which melatonin restrains cancer development and growth have been often described, whereas other roles appear to be merely epiphenomena of a more complex action of melatonin that should be thoroughly investigated. Metastasis is a hallmark of cancer aggressiveness and a major cause of death. It is well-known that to reach the metastatic phenotype the tumor cells use a number of molecular mechanisms including modulating cell adhesion, cytoskeletal organization, extracellular matrix (ECM) interactions, epithelial–mesenchymal transition (EMT) and angiogenesis (4). A key characteristic of a cell in the metastatic process is overcoming cell–cell and cell–ECM adhesions. E-cadherin and occludin are important components of adherens and tight junctions, respectively, and their loss favors tumor metastasis (6,7). Studies using breast (8), gastric (9) and lung (10) cancer cells have shown that melatonin upregulates these proteins, thus reverting their invasive status. Like other cell adhesion proteins, integrins are heterodimeric molecules involved in cell–ECM communication and also influence the migratory potential of cancer cells. In recent studies, melatonin was reported to act against metastasis by reducing the expression of αvβ3 integrin in glioma cells (11) and upregulating β1 integrin in breast cancer cells (12). The cross talk between cadherins and integrins is mediated by the Rho-associated protein kinase (ROCK) and myosin light-chain kinase (MLCK), two key kinases responsible for cytoskeletal reorganization (13). Melatonin is effective by increasing anchorage of invasive cancer cells by organization of ROCK-regulated microtubules and microfilaments (14), and downregulating MLCK and ROCK (10,15). Cell migration to a secondary site also depends on ECM remodeling mediated by matrix metalloproteinases (MMP). In a gastric adenocarcinoma cell line, melatonin inhibited MMP-9 activity by binding and interacting with its active site (16). Additionally, melatonin targeted cytoplasmic Akt/ERK/JNK pathways by reducing MMP-9 transcription dependent of nuclear factor kappa B (NF-κB) (17). The transformation process of a cell from its adherent epithelial state to a migratory mesenchymal phenotype involves rearrangement of cytoskeleton, loss of apical-basal polarity and cell–cell junctions and is mediated by a number of signaling pathways, such as NF-κB, Wnt, Notch, Hedgehog and AP-1 (4,18). NF-κB transactivation can influence the EMT by interacting with transcription factors (Snail, Slug, Twist and Zeb) which downregulate E-cadherin (19) and by induction of vimentin expression, which favors mesenchymal cell transformation (20,21). Melatonin is a promising agent that interferes with NF-κB signaling, even decreasing vimentin expression in breast cancer cells (22). Melatonin also modulates the activation of glycogen synthase kinase 3β (GSK3β), a component of the destruction complex, formed in the absence of Wnt pathway signaling, thus inducing β-catenin dissociation and, consequently, stopping the EMT (23). Drug resistance is one of the biggest challenges regarding cancer, particularly in ovarian carcinomas; this enhances patient’s morbidity and mortality and reduces the efficacy of standard chemotherapies. When used as an adjuvant therapeutic, melatonin enhanced HeLa cervical cancer cells sensitivity to cisplatin through accumulation of damaged DNA and, consequently, increasing the apoptosis ratio (24). Studying colorectal cancer cells, Gao et al. (25) observed that melatonin enhanced the chemotherapeutic effects of 5-fluorouracil (5-FU), one of the most common agents used to treat colorectal cancer; this involved inhibition of NF-κB/iNOS, E-cadherin/MMP9, PI3K/AKT and caspase/PARP pathways. Notably in these cells, melatonin demonstrated a wide range of actions such as anti-proliferative, pro-apoptotic and anti-migration. Melatonin inhibits tumor growth and induces apoptosis in various types of cancer. In prostate cancer models (LNCaP cell line and TRAMP murine model), melatonin induced antitumor activities dependent on IGFBP3 and ERK1/2 signaling; in these cells, melatonin blocked the translocation of androgen receptor, thus documenting its anti-androgenic effects (26). An earlier study by Quintana et al. (27) demonstrated that melatonin, at a 1 mmol/l concentration, was sufficient to improve the cytotoxicity of hyperthermia in U937 human leukemia cells; the indole enhanced the apoptotic effect through activation of caspase-2, -3, -8 and -9, in addition to increasing hyperthermia-induced Bid activation, Bax translocation and cytochrome c release. Following the treatment of rhabdomyosarcoma cell lines with the indoleamine, Codenotti et al. (28) observed fragmentation of DNA and disruption of cell membranes, changes commonly found in apoptotic cells. Using SGC7901 gastric cancer cells, a recent study by Li et al. (29), described the involvement of melatonin in increasing the expression of phosphorylated (p)-p38 and p-JNK proteins, in addition to a decrease in the level of p65. To achieve significant efficacy on the apoptotic index following 24 h of treatment, the optimal dose of melatonin was determined to be 2 mM. In pancreatic cancer, melatonin induces apoptosis through a series of mechanisms, which include mitogen-activated protein kinase (MAPK) pathways; this results in an increased activation of JNK and ERK, suppression of NF-κB, overexpression of caspase-3 and phosphorylation of apoptosis-related proteins like Bax and Bcl-2 (30). By enhancing the expression of p21 and the Bax/Bcl-2 ratio, melatonin triggers apoptosis in breast cancer cells (31). Melatonin also induces apoptosis in LoVo colorectal cancer cells by binding to calmodulin (CaM), and then acting as an antagonist of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, which in turn induces the translocation of the histone deacetylase 4 (HDAC4) to the nucleus (32). When administered alone or in combination with other agents, melatonin has already been shown to be effective against cancer, acting in synergism with standard and novel anticancer therapies to counteract tumor growth and angiogenesis. Indeed, when melatonin was used as an adjuvant for arsenic trioxide (ATO) treatment, it inhibits the growth of breast cancer cells via induction of p21 expression, leading to G1 cell cycle arrest and suppression of human telomerase reverse transcriptase (hTERT) and Myc proto-oncogene protein (c-Myc) (31). Using melatonin to treat gastric cancer cells with overexpressed nuclear RZR/ROR receptors, Wang et al. (33) reported its anti-angiogenic and growth inhibitory effects. In this case, the indoleamine reduced the expression of RZR/ROR receptors and targeted vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1-alpha (HIF-1α) and sentrin-specific protease 1 (SENP1), which are essential to angiogenesis and the spread of tumorigenic cells. In pharmacological concentrations, melatonin is effective in inhibiting HIF-1α and VEGF expression in HepG2 hepatocarcinoma cells, thus reducing its invasive potential (34). Recently, González et al. (35) showed that melatonin inhibits VEGF expression and secretion in SH-SY5Y human neuroblastoma cells co-cultured with endothelial cells. Importantly, the destabilization of the transcriptional factor HIF-1α and, consequently, the reduction of VEGF expression seem to be the major events by which melatonin acts against angiogenesis; however, its effects involving the reduction of the vasoconstrictor endothelin-1 via forkhead box protein O1 (FoxO1) and NF-κB inactivation and inhibition of the ERK/Akt/NF-κB pathway have also been proposed (4). A series of novel studies clarified the role of melatonin in influencing gene expression, particularly acting as an epigenetic modulator. Hardeland (36) summarized different possible epigenetic mechanisms of melatonin regulating both core and accessory oscillating genes, such as Per2 or Clock and Sirt1 and PPAR-γ. Additionally, a new perspective of melatonin effects against cancer has been suggested by reports of miRNA regulations on breast cancer cells (37,38). More specifically, melatonin treatment effectively downregulated miR-24, an important oncogenic miRNA that reduces the activity of p38–p53 axis components involved in DNA repair and inhibition of cell proliferation (38). Curiously, these results may indicate the signaling pathway by which melatonin enhance p53 expression after activation of its receptors, MT1 and MT2, a condition that was previously reported by Santoro et al. (39). Given that multiple molecular pathways have been uncovered related to the anticancer effects of melatonin, a complete understanding on how this indoleamine properly orchestrates such functions is yet far from being fully established. Ovarian cancer: origin, subtypes and conventional treatments Among gynecological malignancies, OC remains the leading cause of death worldwide (40). Unfortunately, OC presents with a poor prognostic outcome for patients diagnosed at a late stage (with a 5-year survival rate of 35%), and there is no screening method for early detection. The primary OCs are classified into epithelial, mesenchymal, germ cell and sex cord-stromal origin. About 90% of OC subtypes originate from ovarian surface epithelium (OSE) or even from distal fallopian tube epithelial cells, with ~70% of cases diagnosed with widespread metastasis (41). These malignant OCs are further subclassified into serous, mucinous, endometrioid and clear cell carcinomas (42), and show particular features of its pathophysiological, genetic and molecular components (43). To date, debulking surgery with chemotherapy or neoadjuvant chemotherapy followed by interval debulking represent the gold standard treatment for OC. New promising therapeutic results have been achieved with the use of cytotoxic agents (44). Notably, late diagnosis and the chemoresistance to conventional treatments (platinum- and taxane-based therapies) represent a big limiting factor for treatment, as many women relapse with aggressive disease. Although additional therapies using chemical agents (aromatase inhibitors, anti-estrogens, anti-angiogenic drugs etc.) are recommended for such OC subtype, they are still very far from optimal efficacy (41). The malignant epithelial OCs that are amenable and confined to the ovary for a considerable period of time belong to the Type I group (<25%). Type II tumors are mostly invasive and often spread early to extraovarian regions during their development (45). Although increasing attention has been given to the new interpretation of the etiology of OC based on the integration of multivariate biomarkers, ultrasound and imaging/screening diagnostics (46), the lack of shared genetic mutations involving specific signaling pathways makes it difficult to extrapolate proper target-based therapies for OC. Although molecular alterations involving specific genetic mutations (e.g. TP53, BRCA1 and 2, proto-oncogene B-Raf and GTPase Kras) are critical for the development of different OC subtypes, epidemiological factors, including exposure to steroid hormones, number of pregnancies, age at menarche and menopause, and hormone replacement therapy, are also relevant to OC risk and management (47,48). It is important to note that drugs targeting specific molecular signatures in tumor cells could be used alone or in combination with existing therapies to ensure clinical improvement for women with OC. Therefore, therapeutic modalities using OC cells or animal models of OC that recapitulate their human counterparts are urgently needed. Based on current evidences, melatonin’ actions can be reproduced with significant implications in both prevention and treatment of tumors, including OC. The variability of its in vitro anticancer effect depends on the conditioning of the cell culture medium, cell differentiation and sensitivity to oncogenic particles; melatonin’ in vivo effects are surely complex and multifaceted into the wide biological context (49). Based in the properties of melatonin, the molecular dynamics on how a normal or tumor cell divides are also dependent on successive events that involve the action of melatonin on circadian time-markers (3). General overview of the role of melatonin on OC In normal ovary, melatonin is secreted by the granulosa cells of preovulatory follicles. In addition, melatonin treatment influences sex steroid production essential for ovulation, luteal function and oocyte quality (50). Melatonin is a powerful free radical scavenger and stimulates the activity of antioxidant enzymes in the ovary (51–53). To explain the primary origin of OC, a recent study revealed that generation of reactive oxygen species (ROS) during ovulation might be responsible for the transformation of tubal fimbria cells with p53 loss, whereas melatonin abolished the tumorigenic effect induced by ROS (54). In support of these findings, a retrospective study involving 277 women with OC showed low serum levels of melatonin compared with those in healthy women (41.8 versus 82.4 pg/ml, respectively). Even though melatonin levels in perimenopausal and postmenopausal women exhibit only minor changes (55), there may be a protective effect of melatonin on the development of OC during this reproductive stage. Although no clear relationship between a woman’s urinary melatonin level and OC risk exists (56), in vitro and in vivo experimental evidence indicates that melatonin may represent a significant therapy against OC. Figure 1 summarizes the most general processes that are regulated by melatonin in different OC subtypes. Figure 1. Open in new tabDownload slide The figure summarizes some processes whereby melatonin has inhibitory action on important molecular mechanisms involved in OC progression. Additional effects of melatonin are also expected following its co-administration with other standard chemotherapeutics (e.g. platinum compounds and taxol derivatives) thereby reducing resistance and improving chemosensitivity to treatment. Figure 1. Open in new tabDownload slide The figure summarizes some processes whereby melatonin has inhibitory action on important molecular mechanisms involved in OC progression. Additional effects of melatonin are also expected following its co-administration with other standard chemotherapeutics (e.g. platinum compounds and taxol derivatives) thereby reducing resistance and improving chemosensitivity to treatment. Melatonin has well-described actions via MT1/MT2 membrane receptors, nuclear receptors (ROR/RZR), calmodulin binding and as a ubiquitous free-radical scavenger (57). Recent advances showed that MT1 activation is responsible for the oncostatic role of melatonin, which results in inhibition of cAMP synthesis and depletion of protein kinase A, C and MAPKs (58). This regulation can negatively influence the expression of genes involved in angiogenesis, proliferation and metastasis after preventing the phosphorylation of a transcription factor dependent on cAMP activity (57). Interestingly, the expression of MT1 is higher in normal ovarian IOSE 364 cells than in OC SKOV-3 and OVCAR-3 cells (58), and exogenous nanomolar concentrations of melatonin upregulate MT1 expression (59). These latter workers also described an intimate relationship between melatonin and estrogen receptors, where estrogens downregulate melatonin receptors and melatonin downregulates estrogen receptors. MT1 is generally found to be reduced in serous papillary OC, and recently, we identified an upregulation of MT1 levels in OC-bearing animals following melatonin treatment (41). These data suggest an important, albeit not fully understood, role of melatonin associated to MT1 pathway in oncogenesis, particularly in OC. Because of its low density, the function and pharmacology of melatonin receptors have been difficult to define in a variety of animal tissues, especially for the MT2 (60). Considering the efficacy and lack of selectivity of the ligands, melatonin or its analogues can act by simultaneous activation of MT1/MT2 heterodimers expressed in a variety of cells; this could promote additive, synergistic or even antagonist actions (61). This is important for cancer prevention and inhibition, as discussed by Liu et al. (60), who reported that MT1 and MT2 agonists inhibited the proliferation of breast cancer MCF-7 cells, whereas the antiproliferative effect of melatonin was abolished following treatment with MT1 and MT2 antagonists. Specific tumorigenic pathways targeted by melatonin in OC cell Figure 2 illustrates the possible signaling pathways by which melatonin probably differentially regulates important cellular events in OC. Melatonin has been described as a potent oncostatic agent with pro-apoptotic, antioxidant and anti-angiogenic effects (62). The oncostatic effect of melatonin was previously reported by Petranka et al. (63) using an ovarian carcinoma cell line (BG-1); in this work, melatonin and the CGP52608, a melatonin nuclear orphan receptor (RZR) agonist, were effective in reducing cell growth in addition to having an impact on apoptosis. Figure 2. Open in new tabDownload slide Schematic representation for the role of melatonin at different therapeutic targets in OC cells. Melatonin has both membrane and intracellular actions that lead to inhibition of cell proliferation, survival, migration, inflammation and angiogenesis of OC. This regulation may directly involve intracellular targets or it may occur indirectly via MT1 receptors. Negative or positive signals indicate downregulation or upregulation resulting from melatonin therapy, respectively. X identifies pathways that are blocked by melatonin. Mel, melatonin; MT1, melatonin receptor 1; ROS, reactive oxygen species; p53, tumor suppressor protein p53; BAX, Bcl-2-like protein 4; NF-kB, nuclear factor kappa B; IRF3, interferon regulatory factor 3; TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 88; TRIF, TIR-domain-containing adapter-inducing interferon-β; VEGF, vascular endothelial growth factor; HIF-1α, hypoxia-inducible factor 1α; HER-2 human epidermal growth factor receptor 2; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; Ras/Raf, protein kinases; MEK, p38MAPK, P38 mitogen-activated protein kinase; ERK1/2, extracellular-signal regulated kinases 1 and 2; MKP3, mitogen-activated protein kinase phosphatase-3; HSP27, heat-shock protein 27; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; G1 and S, phases of the cell cycle. Figure 2. Open in new tabDownload slide Schematic representation for the role of melatonin at different therapeutic targets in OC cells. Melatonin has both membrane and intracellular actions that lead to inhibition of cell proliferation, survival, migration, inflammation and angiogenesis of OC. This regulation may directly involve intracellular targets or it may occur indirectly via MT1 receptors. Negative or positive signals indicate downregulation or upregulation resulting from melatonin therapy, respectively. X identifies pathways that are blocked by melatonin. Mel, melatonin; MT1, melatonin receptor 1; ROS, reactive oxygen species; p53, tumor suppressor protein p53; BAX, Bcl-2-like protein 4; NF-kB, nuclear factor kappa B; IRF3, interferon regulatory factor 3; TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 88; TRIF, TIR-domain-containing adapter-inducing interferon-β; VEGF, vascular endothelial growth factor; HIF-1α, hypoxia-inducible factor 1α; HER-2 human epidermal growth factor receptor 2; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; Ras/Raf, protein kinases; MEK, p38MAPK, P38 mitogen-activated protein kinase; ERK1/2, extracellular-signal regulated kinases 1 and 2; MKP3, mitogen-activated protein kinase phosphatase-3; HSP27, heat-shock protein 27; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; G1 and S, phases of the cell cycle. Treatment with melatonin, varying from 400 to 600 µM, reduced the survival and proliferation rates of two OC cell lines (OVCAR-429 and PA-1), increasing the number of cells in G1 phase and decreasing the number in S phase of the cycle (64). Previously, Kim et al. (65) reported an elevated number of SKOV-3 cells in G1 phase after use of melatonin as a cotreatment with cisplatin. Cyclin-dependent kinases (CDKs) have key roles in cell cycle during phosphorylation of the retinoblastoma protein (pRb). Melatonin efficiently downregulated CDKs, especially CDK2 and 4, in two OC cell lines, thus triggering cell cycle arrest (Figure 2). Additionally, melatonin enhanced the levels of p53, a classical tumor suppressor protein, and p27, a member of CIP/KIP family that inhibits complexes to allow pRb phosphorylation (64). According to Futagami et al. (66), the antiproliferative effect of melatonin has also been shown by its ability to increase the sensitivity to cis-diamminedichloroplatinum (CDDP) in two human OC cell lines (HTOA and OVCAR-3). When associated to CDDP, melatonin at physiological concentrations of 10−6 and 10−9 exhibited an antiproliferative effect in HTOA and OVCAR-3 cells, respectively; in the OVCAR-3 cells, melatonin further reduced telomerase activity, thus suggesting that melatonin changes anti-cancer drug sensitivity and cell survival. Recently, the interplay between melatonin and different extracellular matrices has indicated different responses on proliferation and stemness of SKOV-3 cells. Through its anti-invasive activities, melatonin (0.1 mM) decreased the number of viable cells, colony formation and percentage of stem-like cells in all available matrices (fibronectin, gelatin, matrigel and collagen); these cellular behaviors are thought to have an involvement with upregulation of E-cadherin and downregulation of VEGF (67). Extracellular signal-regulated kinase (ERK) is activated by Raf and is responsible for phosphorylating 90-kDa ribosomal S6 kinases (p90RSKs) for anti-apoptotic regulation (68). RSKs are expressed in a number of cancer types where they are closely related to tumorigenesis (69,70). In addition to their anti-apoptotic role, RSKs can directly interact with heat-shock protein 27 (HSP27) to promote cancer cell survival (65). When administered alone, melatonin (2 mM) does not interfere with p90RSKs and HSP27 levels, but did accelerate HSP27 dephosphorylation in SKOV-3 cells treated with cisplatin. This may in turn inhibit the phosphorylation of p90RSKs and ERK, thus restoring important apoptotic mechanisms in tumor cells. Although p90RSKs and HSP27 are co-expressed and co-localized in untreated SKOV-3 cells, the combination of cisplatin and melatonin suppressed their co-localization, documenting that melatonin may induce apoptosis via inhibition of the ERK/p90RSKs/HSP27 anti-apoptotic pathway (65). In SKOV-3 cells, the combination of cisplatin with melatonin induced caspase-3 activation and cleavage of poly-(ADP-ribose) polymerase (PARP), increasing the cisplatin-induced apoptosis together with elevated levels of MKP3, a specific phosphatase that controls MAPK activation (65). We recently verified the effect of long-term melatonin therapy on the pro-apoptotic (p53, BAX, total and cleaved caspase-3) and anti-apoptotic (Bcl-2 and survivin) proteins in an in vivo model of OC. Melatonin promoted upregulation of p53, BAX and activated caspase-3 followed by DNA fragmentation as observed by TUNEL-positive nuclei. Although Bcl-2 was unaltered, the survivin levels were reduced after melatonin therapy (71), identifying one of the possible routes by which melatonin causes OC cell apoptosis (Figure 2). A recent publication revealed that exogenous melatonin treatment for 60 days efficiently reduced OC mass and the incidence of malignant tumors (e.g. high-grade serous papillary, sarcoma and undifferentiated carcinoma) in an ethanol-preferring rat model. These OCs also exhibited soft and mobile tissues with no peritoneal adhesions (72). To investigate whether melatonin activates human epidermal growth factor receptor (HER) and its downstream targets, the two major subtypes that occur in many cancers, termed HER-2 and HER-4, were studied. In OC cells, HER-2 and HER-4-mediated signaling pathways are strongly related to tumor survival, progression and metastasis. Notably, intraperitoneal administration of long-term melatonin (200 µg/100 body weight/day) efficiently suppressed the OC-related increase in the levels of HER-2, protein kinase B (phospho-Akt), mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) (73), thus demonstrating its probably potential as an adjuvant therapy (Figure 2). Toll-like receptors (TLRs) are a family of active molecules involved in host defense. Emerging evidence suggests TLRs are associated with cancer development in the context of microbial infection, inflammation, injury and tissue repair (74). They are expressed on the surface of OC cells, where especially the TLR2 and TLR4 are associated with chemoresistance to drugs and poor prognosis. Interestingly, melatonin treatment for 60 days induced downregulation of TLR4 and its downstream molecules including myeloid differentiation factor 88 (MyD88), TLR-associated activator of interferon (TRIF), nuclear factor-kappa B (NF-κB p65), inhibitor of NF-κB alpha (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), interferon regulatory factor 3 (IRF3), interferon β (IFN-β), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) (2). Melatonin therapy attenuated the inflammatory response in OC cells through inhibition of either canonical or non-canonical signaling pathways, which may reduce the resistance to the effects of other drugs (Figure 2). Angiogenesis is essential for OC progression and metastasis and molecules with anti-angiogenic capacities typically reduce tumor growth. Hypoxia-inducible factor 1 (HIF-1) is considered a poor prognostic factor and a promising target for the treatment of OC (71). There is considerable evidence showing that melatonin treatment significantly reduces the activity and expression of HIF-1α in both in vitro and in vivo tumors (71,75). In xenograft model of breast cancer, melatonin significantly reduced vascular endothelial growth factor receptor 2 (VEGFR2) together with a reduction in micro-vessel density (76). Similarly, our recent results showed that long-term administration of melatonin downregulated VEGF, TGFβ-1, VEGFR2 and HIF-1α in an animal model of DMBA-induced OC, in addition to having an important effect against neovasculogenesis (Figure 2). These anti-angiogenic effects seem to involve MT1 activation (77). In a recent study, we used quantitative proteomic analysis to obtain new insights into the broad cellular effects of melatonin in an in vivo model of OC. Although no apparent histopathological changes were observed in the serous papillary architecture, melatonin downregulated proteins involved in diverse metabolic systems, including those associated with generation of metabolites and cell energy, HIF-1 signaling, endoplasmic reticulum stress-associated pathways, antigen processing and presentation, and cancer-related proteoglycans. The downregulated proteins related to mitochondrial processes and include glyceraldehyde-3-phosphate dehydrogenase, fructose-bisphosphate aldolase A, pyruvate kinase isozymes M1/M2, malate dehydrogenase, l-lactate dehydrogenase (LDH) A chain, protein disulfide isomerase (PDI) A3 and A6, creatine kinase B, ATP synthase subunit α, 78-kDa glucose-regulated protein (GRP78) and peptidyl-prolyl cis-trans isomerase A. These metabolic alterations may markedly affect aerobic glycolysis (Warburg effect) resulting in low proliferation and reduced metastatic potential of the cells. A few molecules were overexpressed and include ATP synthase subunit β, fatty acid-binding protein and 10-kDa heat-shock protein (78). Melatonin has beneficial effects in combination with OC therapies In 2000, a brief investigation by Bartsch et al. (79) reported that melatonin (varying from 10−6 to 10−10 M) and pineal extract YC05R (500 and 1000 Da) inhibited the growth of cultured primary OC cell obtained from patients with advanced disease. The physiological concentration of melatonin (10−9 M) was even more potent than cisplatin in terms of sensitivity and cell growth. Melatonin is commonly used to quell the adverse effects of concurrent chemotherapy. An interesting paper by Jang et al. (80) described the protective effect of melatonin on the ovarian follicles of cisplatin-induced mouse ovaries. Besides preventing the disruption of follicular reserve via suppression of phosphorylation of PTEN/AKT/FOXO3a signaling pathway, melatonin (at dose of 15 or 30 mg/kg for 3 days) reduced the adverse effects of cisplatin. Thus, melatonin is indicated for use in combination with chemotherapy for young female cancer patients. Of great significance, platinum- and taxol-based chemotherapeutic agents for OC work as a first approach, but the tumors often become resistant to chemotherapy. The combination of chemotherapeutic agents with low cytotoxicity along with photodynamic therapy (PDT) can be applied as a promising strategy to overcome this problem. Melatonin enhances the generation of ROS at pharmacological concentrations in cancer cells in contrast to its well-known free radical-scavenging actions in normal cells (81). The combination of melatonin and PDT in SKOV-3 cells leads to a high production of ROS, and the induction free-radical mediated apoptosis of tumor cells (82). In addition to its well-recognized oncostatic effect, co-administration of melatonin decreases anxiety-like symptoms, depression and general toxicity arising from chemotherapy (83,84). Concluding remarks Searching for molecules that substantially alter these important signaling pathways may be relevant to the treatment of OC. In this perspective, melatonin has added significant contributions to improve functional outcomes in in vitro and in vivo studies, demonstrating its ability to act as combination adjuvant in other therapeutic opportunities for OC. On the basis of why melatonin should be used for cancer treatments, it seems possible that melatonin acts killing damaged cells while promoting survival of injured normal cells. Considering that current clinical treatments are sometimes limited and there is no consistent evidence for efficacy in reducing stable solid tumors following chemotherapy alone, we strongly encourage consideration of the associated use of melatonin in the oncotherapeutic possibilities for OC. The potential of melatonin as a natural molecule also supports its efficacy in reducing adverse effects arising from conventional OC treatments. Although this important role has long been known, it has not been properly exploited at the clinical level. Considering that melatonin is an endogenously produced molecule with no toxicity and is available at pharmaceutical grade purity for humans, the use of melatonin may be helpful in the treatment of OC. Funding This work was not supported by a specific grant from any funding agency. Conflict of Interest Statement: None declared. Abbreviations 5-FU 5-fluorouracil AKT protein kinase B ATO arsenic trioxide Bax apoptosis regulator Bcl-2 family of apoptosis regulators Bid BH3 interacting-domain death agonist B-Raf proto-oncogene CaM calmodulin CaMKII Ca2+/calmodulin-dependent protein kinase II cAMP cyclic adenosine monophosphate CDDP cis-Diamminedichloroplatinum CDKs cyclin-dependent kinases CLOCK clock circadian regulator c-Myc Myc proto-oncogene protein DMBA 7,12-Dimethylbenz[a]anthracene ECM extracellular matrix EMT epithelial-mesenchymal transition ERK1/2 extracellular signal-regulated protein kinases 1 and 2 FOXO1 forkhead box protein O1 GRP78 78-kDa glucose-regulated protein GSK3β glycogen synthase kinase 3β GTPase Kras proto-oncogene HDAC4 histone deacetylase 4 HER epidermal growth factor receptor HIF-1α hypoxia-inducible factor 1-alpha HSP27 heat-shock protein 27 hTERT human telomerase reverse transcriptase IFN-β interferon β IGFBP-3 insulin-like growth factor binding protein-3 IkBα inhibitor of NFkB alpha IKK-α IkB kinase alpha IL-6 interleukin 6 iNOS inducible nitric oxide synthase IRF3 interferon regulatory factor 3 LDH lactate dehydrogenase MAPK mitogen-activated protein kinase miRNA microRNA MKP3 MAP kinase phosphatase 3 MLCK myosin light-chain kinase MMP metalloproteinase MT1 melatonin receptor 1 MT2 melatonin receptor 2 mTOR mammalian target of rapamycin MyD88 myeloid differentiation factor 88 NF-κB nuclear transcription factor-kappa B OC ovarian cancer OSE ovarian surface epithelium P21 cyclin-dependent kinase inhibitor 1 p53 tumor suppressor protein p65 phospho-NF-κB subunit p65 p90RSKs phosphorylating 90-kDa ribosomal S6 kinases PARP Poly (ADP-ribose) polymerase PDI protein disulfide isomerase PDT photodynamic therapy PER2 period circadian clock 2 PI3K phosphoinositide 3-kinase p-JNK phospho-c-Jun N-terminal Kinase p-p38 phospho-p38 MAPK PPAR-γ peroxisome proliferator-activated receptor gamma pRb retinoblastoma protein PTEN phosphatase and tensin homolog ROCK Rho-associated protein kinase ROS reactive oxygen species RSKs ribosomal S6 kinases RZR/ROR orphan receptors family SENP1 sentrin-specific protease 1 Sirt1 sirtuin 1 TGFβ-1 transforming growth factor beta-1 TLRs toll-like receptors TNF-α tumor necrosis factor alpha TP53 p53 gene TRAF6 TNF receptor-associated factor 6 TRIF TLR-associated activator of interferon VEGF vascular endothelial growth factor VEGFR2 vascular endothelial growth factor receptor 2 References 1. 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TI - Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms
JF - Carcinogenesis
DO - 10.1093/carcin/bgx054
DA - 2017-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/melatonin-as-a-promising-agent-to-treat-ovarian-cancer-molecular-0v0jJffAYu
SP - 945
VL - 38
IS - 10
DP - DeepDyve
ER -