Melatonin May Increase Anticancer Potential of Pleiotropic Drugs

Melatonin (N-acetyl-5-methoxytryptamine) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. Numerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one of the most aspiring goals in cancer prevention/therapy. A link between cancer and inflammation and/or metabolic disorders has been well established and the therapy of these conditions with so-called pleiotropic drugs, which include non-steroidal anti-inflammatory drugs, statins and peroral antidiabetics, modulates a cancer risk too. Adjuvant therapy with melatonin may improve the oncostatic potential of these drugs. Results from preclinical studies are limited though support this hypothesis, which, however, remains to be verified by further research

Effect of a Short-Term and Long-Term Melatonin Administration on Mammary Carcinogenesis in Female Sprague-Dawley Rats Influenced by Repeated Psychoemotional Stress

The aim of this study was to evaluate the effect of melatonin (MEL) on N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in female Sprague-Dawley rats exposed to repeated psychoemotional stress - immobilization in boxes. NMU was applied intraperitoneally in two doses each of 50 mg/kg b.w. between 40 - 50 postnatal days. Melatonin was administered in drinking water at a concentration of 4 μg/ml daily from 15:00 h to 8:00 h. The application was initiated 5 days prior to the fi rst NMU dose and lasted 15 days, i.e. during the promotion phase of tumour development, or long-term until the end of the experiment (week 20). Immobilization (2 h per day) began on the third day after the second carcinogen application and lasted for 7 consecutive days. Short-term MEL administration to immobilized animals increased incidence by 22%, decreased tumour frequency per animal by 26% and reduced tumour volume gain (by 21%) when compared to the immobilized group without MEL application. Decreased frequency per animal by 28% and more than a 40% decrease in tumour volume gain and cumulative volume were the most pronounced changes in the animals drinking MEL until the end of the experiment. Long-term MEL administration reduced the number and size of mammary tumours more markedly than its short-term administration. Melatonin decreased certain attributes of mammary carcinogenesis in female rats influenced by psychoemotional stress

The Impact of Hyperglycemia on VEGF Secretion in Retinal Endothelial Cells

AbstractBackground:Diabetic retinopathy is a serious sight-threatening complication which is manifested by excessive angiogenesis in diabetic patients.Aim:We hypothesize that cultured Rhesus monkey retinal endothelial cells (RhRECs) respond to high glucose with a change in cell proliferation and vascular endothelial growth factor (VEGF) secretion.Materials and methods:In our study, 20 000 cells per well were treated without glucose or with 5.5 mM, 18.5 mM and 30 mM glucose for 24 hours. Viable cells were counted using trypan blue dye exclusion method. VEGF concentrations were measured in cell media by ELISA method.Results:The number of viable cells incubated with 5.5 mM glucose increased significantly by 53.7% after 24 hours. In comparison, the number of viable cells decreased by 2.8% at 18.5 mM of glucose and by 20.4% at 30 mM of glucose after 24 hours of incubation. In contrast to this effect of glucose on the number of viable cells, a significant increase in VEGF levels (pg/mL) in the cell media with a glucose concentration of 0 mM compared to 5.5 mM of glucose was found. VEGF secretion in cell medium with 18.5 and 30 mM of glucose increased non-significantly in comparison with euglycemic levels.Conclusion:Our results show that viability of retinal endothelial cells and VEGF release are highly responsive to changes in glucose concentration. Such glucose-induced changes in retinal endothelial cells may negatively impact the integrity of the microvasculature in the diabetic retina leading to angiogenesis and microaneursym.</jats:p

Chemoprevention of N-Methyl-N-Nitrosourea Induced Mammary Carcinogenesis with Raloxifene and Melatonin: Metabolic Changes in Female Rats

Abstract Chamilová M., P. Kubatka, K. Kalická, E. Adámeková, B. Bojková, I. Ahlers, E. Ahlersová: Chemoprevention of N-methyl-N-nitrosourea Induced Mammary Carcinogenesis with Raloxifene and Melatonin: Metabolic Changes in Female Rats. Acta Vet. Brno 2002, 71: 235-242. The aim of this work was to determine the selected parameters of carbohydrate and lipid metabolism in the mammary carcinogenesis induced with N-methyl-N-nitrosourea (NMU) in two doses, each by 50 mg/kg of body weight with a 7-day interval between them within the postnatal days 43 and 54 in female Sprague-Dawley rats. Chemoprevention started with the administration of melatonin (MEL, 4 µg/ml in water, from 15.00 h to 08.00 h) 12 days and raloxifene (RAL 5 mg/kg, 2 × weekly) 10 days before the application of NMU. Twenty-four weeks following the NMU administration the animals were killed, and the incidence, latency, frequency and volume of tumours were evaluated. The animals were divided into: tumour-bearing (TB) and non-tumourbearing (NTB) with the influence of RAL, MEL and their combination. While RAL and RAL plus MEL significantly decreased the incidence and frequency of tumours, the effect of isolated MEL was substantially lower. In the serum, an increase in the concentration of serum glucose in TB and also NTB animals was observed. In the liver of both the TB and NTB animals, the content of cholesterol (CH) and triacylglycerols (TG) decreased and the contents of phospholipids (PL) increased. RAL decreased the contents of CH and PL in the liver of NTB animals and increased the concentration of TG in both groups of animals. Administration of RAL to NTB animals decreased the concentrations of malondialdehyde (MDA) in the serum and thymus, in the bone marrow also in TB animals. MEL decreased the concentration of MDA in the bone marrow of TB animals. MEL increased the concentrations of serum glucose and glycogen content in the heart muscle of NTB animals. RAL plus MEL decreased the concentration of serum TG and PL and decreased the contents of CH and PL in the liver of TB as well as NTB animals. In the thymus and liver, combination of RAL+MEL decreased the MDA content compared with the RAL alone in NTB animals. The co-effect of two or more substances will be probably the optimal way in prevention of cancer. The co-effect of RAL and MEL shows to be a prospective way for influencing the mammary tumors. Breast cancer, female rats, raloxifene, melatonin, chemoprevention The hormonal therapy of the breast carcinoma is an inseparable part of the variety of therapeutic procedures. The substitution with estrogens has been considered for a long time as a dominant indication of therapy in postmenopausal women, and it has been recognized that approximately one third of women will have a benefit of this procedure. The use of estrogens protects these women against osteoporosis and decreases the cardiovascular risk, but on the other hand, increases the risk of breast and endometrium carcinom

Caution, "normal" BMI: health risks associated with potentially masked individual underweight - EPMA position paper 2021

An increasing interest in a healthy lifestyle raises questions about optimal body weight. Evidently, it should be clearly discriminated between the standardised "normal" body weight and individually optimal weight. To this end, the basic principle of personalised medicine "one size does not fit all" has to be applied. Contextually, "normal" but e.g. borderline body mass index might be optimal for one person but apparently suboptimal for another one strongly depending on the individual genetic predisposition, geographic origin, cultural and nutritional habits and relevant lifestyle parameters - all included into comprehensive individual patient profile. Even if only slightly deviant, both overweight and underweight are acknowledged risk factors for a shifted metabolism which, if being not optimised, may strongly contribute to the development and progression of severe pathologies. Development of innovative screening programmes is essential to promote population health by application of health risks assessment, individualised patient profiling and multi-parametric analysis, further used for cost-effective targeted prevention and treatments tailored to the person. The following healthcare areas are considered to be potentially strongly benefiting from the above proposed measures: suboptimal health conditions, sports medicine, stress overload and associated complications, planned pregnancies, periodontal health and dentistry, sleep medicine, eye health and disorders, inflammatory disorders, healing and pain management, metabolic disorders, cardiovascular disease, cancers, psychiatric and neurologic disorders, stroke of known and unknown aetiology, improved individual and population outcomes under pandemic conditions such as COVID-19. In a long-term way, a significantly improved healthcare economy is one of benefits of the proposed paradigm shift from reactive to Predictive, Preventive and Personalised Medicine (PPPM/3PM). A tight collaboration between all stakeholders including scientific community, healthcare givers, patient organisations, policy-makers and educators is essential for the smooth implementation of 3PM concepts in daily practice

Tamoxifen and oxidative stress: an overlooked connection

Tamoxifen is the gold standard drug for the treatment of breast cancer in pre and post-menopausal women. Its journey from a failing contraceptive to a blockbuster is an example of pharmaceutical innovation challenges. Tamoxifen has a wide range of pharmacological activities; a drug that was initially thought to work via a simple Estrogen receptor (ER) mechanism was proven to mediate its activity through several non-ER mechanisms. Here in we review the previous literature describing ER and non-ER targets of tamoxifen, we highlighted the overlooked connection between tamoxifen, tamoxifen apoptotic effects and oxidative stress

Dietary phytochemicals in breast cancer research: anticancer effects and potential utility for effective chemoprevention

Abstract Cancerous tissue transformation developing usually over years or even decades of life is a highly complex process involving strong stressors damaging DNA, chronic inflammation, comprehensive interaction between relevant molecular pathways, and cellular cross-talk within the neighboring tissues. Only the minor part of all cancer cases are caused by inborn predisposition; the absolute majority carries a sporadic character based on modifiable risk factors which play a central role in cancer prevention. Amongst most promising candidates for dietary supplements are bioactive phytochemicals demonstrating strong anticancer effects. Abundant evidence has been collected for beneficial effects of flavonoids, carotenoids, phenolic acids, and organosulfur compounds affecting a number of cancer-related pathways. Phytochemicals may positively affect processes of cell signaling, cell cycle regulation, oxidative stress response, and inflammation. They can modulate non-coding RNAs, upregulate tumor suppressive miRNAs, and downregulate oncogenic miRNAs that synergically inhibits cancer cell growth and cancer stem cell self-renewal. Potential clinical utility of the phytochemicals is discussed providing examples for chemoprevention against and therapy for human breast cancer. Expert recommendations are provided in the context of preventive medicine