• Cancer management
• Melatonin
• Oncology
• Therapeutic potential

• cancer
• melatonin
• synergistic actions
• treatment
• vitamin D

• Humans
• Melatonin/therapeutic use
• Melatonin/pharmacology
• Vitamin D/therapeutic use
• Neoplasms/drug therapy
• Drug Synergism
• Dietary Supplements
• Antioxidants/therapeutic use
• Antioxidants/pharmacology
• Animals

• Endometriosis
• Melatonin
• Oxidative stress
• Pharmacology
• Polycystic ovary syndrome
• Uterine leiomyoma

• Humans
• Female
• Melatonin/pharmacology
• Melatonin/therapeutic use
• Melatonin/metabolism
• Polycystic Ovary Syndrome/drug therapy
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Antioxidants/metabolism
• Oxidative Stress
• Breast Neoplasms/pathology

• Humans
• Female
• Melatonin/metabolism
• Receptor, Melatonin, MT1/metabolism
• Carcinoma, Ovarian Epithelial
• Receptor, Melatonin, MT2/metabolism
• Retrospective Studies
• Ovarian Neoplasms

• Melatonin
• PD-L1
• anti-tumor immunity
• epithelial-mesenchymal transition
• head and neck squamous cell carcinoma

GPCRs and GPCR pathways are increasingly being implicated in human malignancies, placing them among the most promising cancer drug candidates. Our results reveal enrichment of highly impactful, recurrent GPCR mutations within cancers. We found that cognate mutations in selected class A GPCRs have deleterious effects on signaling function. The results also suggest that olfactory receptors, often considered inconsequential, display a nonrandom mutation pattern in tumors in which they are expressed. These findings support the idea that protein paralogs can act in parallel as members of an onco-group.

G protein-coupled receptors (GPCRs) are the largest family of human proteins. They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and effectors, activate downstream pathways that often modulate hallmark mechanisms of cancer. Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling similarly so as to favor a tumor. We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR function are distributed across many receptors. To test this possibility, we systematically aggregated somatic cancer mutations across class A GPCRs and found a nonrandom distribution of positions with variant amino acid residues. Individual cancer types were enriched for highly impactful, recurrent mutations at selected cognate positions of known functional motifs. We also discovered that no single receptor drives this pattern, but rather multiple receptors contain amino acid substitutions at a few cognate positions. Phenotypic characterization suggests these mutations induce perturbation of G protein activation and/or β-arrestin recruitment. These data suggest that recurrent impactful oncogenic mutations perturb different GPCRs to subvert signaling and promote tumor growth or survival. The possibility that multiple different GPCRs could moonlight as drivers or enablers of a given cancer through mutations located at cognate positions across GPCR paralogs opens a window into cancer mechanisms and potential approaches to therapeutics.

• G protein-coupled receptor (GPCR)
• cancer
• evolutionary action (EA)
• mutational signatures
• β-arrestin

Background: Melatonin, produced by the pineal gland, is known for its antioxidant, oncostatic, and anti-inflammatory properties. However, studies on serum melatonin levels in different cancer types have yielded conflicting results, and little is known about the clinical significance of serum melatonin in oral squamous cell carcinoma (OSCC) in the Southern Asian population. Therefore, we explored its role in OSCC in this study. Methods: A total of 67 male OSCC patients and 78 healthy controls were enrolled in this case–control study. The serum levels of melatonin were determined by enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Results: The serum melatonin levels were significantly lower in OSCC patients compared with healthy controls (mean ± standard deviation, 15.0 ± 4.6 vs. 18.5 ± 11.8 pg/mL, p = 0.02). In the subgroup of age less than 55 years (mean age of OSCC), OSCC patients had a significantly decreased melatonin level than healthy controls (mean melatonin, 15.7 ± 12.6 vs. 20.8 ± 3.9 pg/mL, p = 0.02). Decreased serum melatonin (odds ratio (OR): 0.95, 95%CI: 0.91–0.99), alcohol consumption (OR: 29.02, 95%CI: 11.68–72.16), betel quid chewing (OR:136.44, 95%CI: 39.17–475.27), and cigarette smoking (OR:29.48, 95%CI: 11.06–78.60) all increased the risk of OSCC under univariate analyses of logistic regression. Betel quid chewing (OR: 45.98, 95%CI: 10.34–204.49) and cigarette smoking (OR:6.94, 95%CI: 1.60–30.16) were the independent risk factors for OSCC in Taiwan. In addition, a negative correlation between age and melatonin level was observed in healthy controls (Pearson r = −0.24, p = 0.03). However, the negative correlation was lost in patients with OSCC. Melatonin concentration had no association with the severity of OSCC. Conclusion: Overall, our study provides evidence that serum melatonin levels decreased in OSCC patients in Taiwan and the decreased level is much significant in young populations and suggests that the decreased melatonin was associated with OSCC, especially in young populations. Further studies are warranted to investigate whether melatonin can be a useful non-invasive screening tool for OSCC.

• biomarker
• melatonin
• oral cavity squamous cell carcinoma

• HNSCC
• MTHFD1L
• formate
• melatonin
• metabolomics

• Aminohydrolases/genetics
• Aminohydrolases/metabolism
• Cell Line, Tumor
• Formate-Tetrahydrofolate Ligase/genetics
• Formate-Tetrahydrofolate Ligase/metabolism
• Formates
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms
• Humans
• Melatonin/pharmacology
• Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics
• Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism
• Multienzyme Complexes/genetics
• Multienzyme Complexes/metabolism
• Squamous Cell Carcinoma of Head and Neck/genetics

Identifying novel colorectal cancer (CRC) prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions. Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours.

To explore the relationship between MTNR1B single-nucleotide polymorphism (SNPs) combined with gene hypermethylation and CRC prognosis.

A total of 94 CRC tumour tissues were investigated. Genotyping for the four MTNR1B SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) was performed using multiplex polymerase chain reaction. The relationships between the MTNR1B SNPs and CRC 5-year overall survival (OS) was assessed by calculating hazard ratios with 95%CIs.

All SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) were correlated with decreased 5-year OS. In stratified analysis, rs1387153, rs10830963, and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS. MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival.

The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.

• Colorectal cancer
• Melatonin
• Hypermethylation
• Polymorphism
• Prognosis
• Biomarker

• Colorectal Neoplasms/genetics
• Cyclin-Dependent Kinase Inhibitor p16
• DNA Methylation
• DNA Modification Methylases/genetics
• DNA Repair Enzymes/genetics
• Humans
• Polymorphism, Single Nucleotide
• Prognosis
• Receptor, Melatonin, MT2/genetics
• Taiwan/epidemiology
• Tumor Suppressor Proteins/genetics

Oral squamous cell carcinomas (OSCCs) are one of the most prevalent malignancies, with a low five-year survival rate, thus warranting more effective drugs or therapy to improve treatment outcomes. Melatonin has been demonstrated to exhibit oncostatic effects. In this study, we explored the anti-cancer effects of melatonin on OSCCs and the underlying mechanisms. A human tongue squamous cell carcinoma cell line (SCC-15) was treated with 2 mM melatonin, followed by transwell migration and invasion assays. Relative expression levels of Fibroblast Growth Factor 19 (FGF19) was identified by Cytokine Array and further verified by qPCR and Western blot. Overexpression and downregulation of FGF19 were obtained by adding exogenous hFGF19 and FGF19 shRNA lentivirus, respectively. Invasion and migration abilities of SCC-15 cells were suppressed by melatonin, in parallel with the decreased FGF19/FGFR4 expression level. Exogenous hFGF19 eliminated the inhibitory effects of melatonin on SCC-15 cells invasion and migration, while FGF19 knocking-down showed similar inhibitory activities with melatonin. This study proves that melatonin suppresses SCC-15 cells invasion and migration through blocking the FGF19/FGFR4 pathway, which enriches our knowledge on the anticancer effects of melatonin. Blocking the FGF19/FGFR4 pathway by melatonin could be a promising alternative for OSCCs prevention and management, which would facilitate further development of novel strategies to combat OSCCs.

• fibroblast growth factor 19 (FGF19)
• fibroblast growth factor receptor 4 (FGFR4)
• invasion
• melatonin
• migration
• oral squamous cell carcinomas

• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Cell Movement/drug effects
• Cell Survival/drug effects
• Fibroblast Growth Factors/genetics
• Fibroblast Growth Factors/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Melatonin/pharmacology
• Mouth Neoplasms/genetics
• Mouth Neoplasms/pathology
• Neoplasm Invasiveness
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Receptor, Fibroblast Growth Factor, Type 4/genetics
• Receptor, Fibroblast Growth Factor, Type 4/metabolism
• Signal Transduction/drug effects

• Aged
• Antineoplastic Agents/administration & dosage
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/prevention & control
• Female
• Humans
• Incidence
• Male
• Melatonin/administration & dosage
• Middle Aged
• Proportional Hazards Models
• Retrospective Studies
• Risk Factors
• Sensitivity and Specificity
• Sleep Aids, Pharmaceutical/administration & dosage
• Sleep Quality
• Sweden/epidemiology

• cancer
• biomarkers

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/metabolism
• Carcinoma, Squamous Cell/blood
• Carcinoma, Squamous Cell/metabolism
• Case-Control Studies
• Female
• Humans
• Male
• Melatonin/blood
• Melatonin/metabolism
• Middle Aged
• Mouth Neoplasms/blood
• Mouth Neoplasms/metabolism
• ROC Curve
• Saliva/metabolism
• Sleep/physiology

• Hrvatska Zaklada za Znanost

• Cancer-associated fibroblasts
• Gastric cancer
• Melatonin
• NF-κB pathways

• Candidatus Liberibacter asiaticus
• Diaphorina citri
• acetylserotonin methyltransferase (ASMT)
• aromatic L-amino acid decarboxylase (AADC)
• bioinformatics
• citrus
• melatonin
• serotonin N-acetyltransferase (SNAT)
• tryptophan hydroxylase (TPH)

• P41 GM103311 NIGMS NIH HHS

• angiogenesis
• antiangiogenic
• anticancer
• antioxidant
• apoptosis
• chemotherapy
• combination therapy
• melatonin receptors
• metastasis
• molecular mechanisms

Melatonin is one of the most phylogenetically conserved signals in biology. Although its original function was probably related to its antioxidant capacity, this indoleamine has been “adopted” by multicellular organisms as the “darkness signal” when secreted in a circadian manner and is acutely suppressed by light at night by the pineal gland. However, melatonin is also produced by other tissues, which constitute its extrapineal sources. Apart from its undisputed chronobiotic function, melatonin exerts antioxidant, immunomodulatory, pro-apoptotic, antiproliferative, and anti-angiogenic effects, with all these properties making it a powerful antitumor agent. Indeed, this activity has been demonstrated to be mediated by interfering with various cancer hallmarks, and different epidemiological studies have also linked light at night (melatonin suppression) with a higher incidence of different types of cancer. In 2007, the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption, where melatonin plays a central role. Our aim is to review, from a global perspective, the role of melatonin both from pineal and extrapineal origin, as well as their possible interplay, as an intrinsic factor in the incidence, development, and progression of cancer. Particular emphasis will be placed not only on those mechanisms related to melatonin’s antioxidant nature but also on the recently described novel roles of melatonin in microbiota and epigenetic regulation.

• antioxidant
• antitumor
• cancer
• chronobiotic
• circadian
• extrapineal
• immunomodulatory
• light at night
• melatonin
• pineal

Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial–mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and β-catenin. We observed that β-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of β-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the β-catenin/SLUG axis. Furthermore, the expression levels of NE and β-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and β-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/β-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.

• Anti-metastatic
• Anti-proliferative
• Anticancer
• Antioxidant
• Melatonin
• Suprachiasmatic nucleus

• carcinogenicity
• meta-analysis
• night-shift work
• odds ratio
• risk factor

• B16F10 cells
• DNA damage
• Melanoma
• comet assay
• genotoxicity
• melatonin
• micronucleus test
• mutagenicity
• skin cancer

• biomarkers
• matrix metalloproteinase-9
• melatonin
• metastasis
• oral squamous cell carcinoma
• tissue inhibitor of metalloproteinase-1

• biomarker
• melatonin
• metastasis
• oral squamous cell carcinoma

Ovarian cancer is one of the most common causes of morbidity related to gynecologic malignancies. Possible risk factors are including hereditary ovarian cancer, obesity, diabetes mellitus, alcohol consumption, aging, and smoking. Various molecular signaling pathways including inflammation, oxidative stress, apoptosis and angiogenesis are involved in this progression of ovarian cancer. Standard treatments for recently diagnosed patients are Surgery and chemotherapy such as co-treatment with other drugs such that the exploitation of neoadjuvant chemotherapy is expanding. Melatonin (N-acetyl-5-methoxy-tryptamine), an endogenous agent secreted from the pineal gland, has anti-carcinogenic features, such as regulation of estradiol production, cell cycle modulation, stimulation of apoptosis as well as anti-angiogenetic properties, anti-inflammatory activities, significant antioxidant effects and modulation of various immune system cells and cytokines. Multiple studies have shown the significant beneficial roles of melatonin in various types of cancers including ovarian cancer. This paper aims to shed light on the roles of melatonin in ovarian cancer treatment from the standpoint of the molecular aspects.

• Anti-angiogenetic properties
• Anti-inflammatory activities
• Melatonin
• Ovarian cancer
• Signaling pathways

The round-the-clock demands of healthcare services, coupled with the shortage of healthcare providers in many parts of the world, have made shiftwork widespread among healthcare workers. Understanding how to mitigate unfavourable effects of shiftwork on well-being is essential to improve health promotion, to prevent disease prevention, and to increase quality of life. This comprehensive review aims to present evidence linking shiftwork with cardiovascular diseases and cancers among healthcare workers. Several studies have demonstrated evidence indicating the relationship between long-term exposure to shiftwork tempo and a higher risk of cardiovascular diseases. Health workers are increasingly witnesing unfavourable effects of shiftwork on their health state. Shiftwork disturbs circadian rhythm and cardiopulmonary processes, leading to adverse health outcomes. Increasing prevalence of shiftwork in healthcare industries due to population expansion and public health threat of cancers call for investigation towards a better understanding of the underlying mechanism of shiftwork-induced diseases. The shift work period has been considered in different studies using various criteria, resulting in inconsistent definition of measurement criteria leading to misclassification of the study population. There is a need for a more considerable and holistic effort towards standardization of shiftwork definition and conduct an assessment to establish a more conveniently appliacable framework for intervention strategies.

• Shift work
• cancers
• cardiovascular
• healthcare
• rotating shiftwork

Melatonin (MLT), a kind of neuroendocrine active substance, has been reported to function in the treatment of tumors. However, there remain controversies about the curative effect of MLT in tumors in clinical studies. This study investigates the efficacy of MLT on tumor therapeutic strategies by meta-analysis.

After searching several main literature databases, a total of 5,057 articles were obtained and screened by inclusion and exclusion criteria. The tumor remission rate, overall survival rate, and incidence of side effects were recorded and analyzed in the included study patients. Group analysis and sensitivity analysis were performed to examine the sources of heterogeneity in the pooled studies.

The tumor remission rate in the MLT group was significantly higher than that in the control group (relative risk [RR] =2.25; 95% CI, 1.86–2.71; P<0.00001; I²=9%). Likewise, the MLT group had an overall survival rate of 28.24% (n=294/1,041), which was greatly increased compared with the control group (RR =2.07; 95% CI, 1.55–2.76; P<0.00001; I²=55%). And, MLT could significantly enhance the overall survival rate in non-small-cell lung cancer patients (RR =2.13; 95% CI, 1.41–3.24; P=0.0004; I²=0%) and various solid tumor patients (RR =2.31; 95% CI, 1.78–2.99; P<0.00001; I²=0%). It was further proved that MLT could effectively reduce the incidence of neurotoxicity (RR =0.30, 95% CI, 0.19–0.45; P<0.00001), thrombocytopenia (RR =0.23; 95% CI, 0.16–0.33; P<0.00001), and asthenia (RR =0.43, 95% CI, 0.38–0.49; P<0.00001) during chemotherapy.

MLT exerts positive influence in tumor therapeutic strategies, including improving tumor remission rate and overall survival rate, while reducing the incidence of chemotherapy side effects. Further large-scale randomized clinical trials (RCTs) are urgently required to verify therapeutic effects of MLT in tumors by various clinical research centers.

• MLT
• overall survival rate
• side effects of chemotherapy
• tumor remission rate

• Diaphorina citri
• Asian citrus psyllid
• Candidatus Liberibacter asiaticus
• ROS
• free radicals
• longevity
• melatonin
• survival
• vector-borne pathogen

• Animals
• Hemiptera/metabolism
• Hemiptera/microbiology
• Insect Vectors/metabolism
• Insect Vectors/microbiology
• Longevity
• Melatonin/biosynthesis
• Plant Diseases/microbiology
• Rhizobiaceae/metabolism

• anticancer
• apoptosis
• mechanisms of action
• melatonin
• receptor

Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cellular energetics, and immune evasion. Melatonin anticancer activity is mediated by interfering with various cancer hallmarks. This review summarizes the anticancer role of melatonin in each cancer hallmark. The studies discussed in this review should serve as a solid foundation for researchers and physicians to support basic and clinical studies on melatonin as a promising anticancer agent.

• angiogenesis
• anticancer
• cancer hallmarks
• immune evasion
• melatonin
• metastasis

• Angiogenesis Inhibitors
• Animals
• Antineoplastic Agents/pharmacology
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/immunology
• Cell Transformation, Neoplastic/metabolism
• Disease Progression
• Genomic Instability
• Humans
• Melatonin/chemistry
• Melatonin/genetics
• Melatonin/metabolism
• Melatonin/pharmacology
• Metabolic Networks and Pathways
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic
• Signal Transduction/drug effects
• Tumor Escape

Melatonin, a pineal gland hormone, exerts oncostatic activity in several types of human cancer, including prostate, the most common neoplasia and the third most frequent cause of male cancer death in the developed world. The growth of androgen-sensitive LNCaP prostate cancer cells in mice is inhibited by 3 mg/kg/week melatonin (0.09 mg/mouse/week) delivered by i.p. injections, which is equivalent to a dose of 210 mg/week in humans. The aim of this study is to test an alternative noninvasive delivery route based on transdermal administration of melatonin onto the tumor area followed by cryopass-laser treatment. Two groups of immunodepressed mice were studied, one (n = 10) subjected to 18 cryopass-laser therapy sessions and one (n = 10) subjected to the same treatment without melatonin. These groups were compared with mice treated with i.p.-administered melatonin or vehicle with the same time schedule. We found that cryopass-laser treatment is as efficient as i.p. injections in reducing the growth of LNCaP tumor cells, affecting plasma melatonin and redox balance. Furthermore, both delivery routes share the same effects on the involved biochemical pathway driven by hypoxia-inducible factor 1α. However, cryopass-laser, as used in the present experimental setup, is less efficient than i.p delivery route in increasing the melatonin content and Nrf2 expression in the tumor mass. We conclude that cryopass-laser treatment may have impact for melatonin-based therapy of prostate cancer, by delivering drugs transdermally without causing pain and targeting directly on the site of interest, thereby potentially making long-term treatments more sustainable.

• Melatonin
• anticancer activity
• cryopass-laser therapy
• drug delivery
• experimental prostate cancer
• transdermal administration

• angiogenesis
• antioxidant
• apoptosis
• breast
• chemotherapy
• free radicals
• invasion
• ionizing radiation
• melatonin receptors
• molecular mechanisms
• prostate

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Cell Transformation, Neoplastic/drug effects
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/radiation effects
• DNA Damage/drug effects
• DNA Damage/radiation effects
• Disease Progression
• Drug Resistance, Neoplasm
• Genomic Instability/drug effects
• Genomic Instability/radiation effects
• Humans
• Melatonin/metabolism
• Melatonin/pharmacology
• Melatonin/therapeutic use
• Neoplasm Metastasis
• Neoplasms/drug therapy
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Radiation-Protective Agents/pharmacology
• Radiation-Protective Agents/therapeutic use
• Treatment Outcome