Atranorin (ATR) is a secondary metabolite of lichens. While previous studies investigated the effects of this substance predominantly in an in vitro environment, in our study we investigated the basic physicochemical properties, the binding affinity to human serum albumin (HSA), basic pharmacokinetics, and, mainly, on the systematic effects of ATR in vivo. Sporadic studies describe its effects during, predominantly, cancer. This project is original in terms of testing the efficacy of ATR on a healthy organism, where we can possibly attribute negative effects directly to ATR and not to the disease. For the experiment, 24 Sprague Dawley rats (Velaz, Únetice, Czech Republic) were used. The animals were divided into four groups. The first group (n = 6) included healthy males as control intact rats (♂INT) and the second group (n = 6) included healthy females as control intact rats (♀INT). Groups three and four (♂ATR/n = 6 and ♀ATR/n = 6) consisted of animals with daily administered ATR (10mg/kg body weight) in an ethanol-water solution per os for a one-month period. Our results demonstrate that ATR binds to HSA near the binding site TRP214 and acts on a systemic level. ATR caused mild anemia during the treatment. However, based on the levels of hepatic enzymes in the blood (ALT, ALP, or bilirubin levels), thiobarbituric acid reactive substances (TBARS), or liver histology, no impact on liver was recorded. Significantly increased creatinine and lactate dehydrogenase levels together with increased defecation activity during behavioral testing may indicate the anabolic effect of ATR in skeletal muscles. Interestingly, ATR changed some forms of behavior. ATR at a dose of 10 mg/kg body weight is non-toxic and, therefore, could be used in further research.

• Klíčová slova
• atranorin, behavioral changes, human serum albumin, laboratory rats, metabolomics, microsomal stability,
• Publikační typ
• časopisecké články MeSH

The risk of cancer may be modulated by drugs with pleiotropic effects and diet has been implicated in the efficacy of treatment. The oncopreventive effects of the antidiabetic drug pioglitazone (PIO) and the anti-insomnia drug melatonin (MT), in vivo, have been proven before, but using a standard-type diet. This study evaluated the impact of a high-fat diet on their efficacy in chemically induced mammary carcinogenesis in Sprague-Dawley rats. Mammary tumours were induced by N-methyl-N-nitrosourea (50 mg/kg, intraperitoneal, on the 41st postnatal day). PIO and MT administration was initiated 11 days before the carcinogen application and lasted until the termination of the experiment at 16 weeks. PIO was administered in a diet (10% fat) at a concentration of 100 ppm and MT was administered in tap water (20 mg/l). PIO, MT and the combination did not significantly alter the basic tumour growth parameters. However, histopathology showed a decrease in the high-grade/low-grade tumour ratio, particularly in animals that received combined treatment (P<0.01). Semiquantitative immunohistochemistry indicated the proapoptotic effect of chemoprevention, particularly in the drug combination group (P<0.01), but no changes in tumour cell proliferation and angiogenesis were recorded. Results were evaluated by one-way analysis of variance or the Mann-Whitney U-test, respectively. PIO and MT, alone or in combination, administered to rats fed a high-fat diet reduced the proportion of high-grade tumours and promoted apoptosis in an in-vivo breast cancer model, although it did not suppress tumour growth. The impact of high dietary fat content on the chemopreventive efficacy of these and other substances should be considered in human studies.

• MeSH
• antioxidancia farmakologie   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• experimentální nádory mléčných žláz farmakoterapie   etiologie   patologie   MeSH
• hypoglykemika farmakologie   MeSH
• karcinogeny toxicita   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu Rattus MeSH
• melatonin farmakologie   MeSH
• methylnitrosomočovina toxicita   MeSH
• modely nemocí na zvířatech MeSH
• pioglitazon MeSH
• potkani Sprague-Dawley MeSH
• thiazolidindiony farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• hypoglykemika MeSH
• karcinogeny MeSH
• melatonin MeSH
• methylnitrosomočovina MeSH
• pioglitazon MeSH
• thiazolidindiony MeSH

PURPOSE: Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti-tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. METHODS: Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed. RESULTS: High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI-positive MCF-7 cells and DNA fragmentation. CONCLUSIONS: Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities.

• Klíčová slova
• Angiogenesis, Apoptosis, Cell proliferation, Fruit polyphenols, MCF-7, Mammary carcinogenesis, Rat,
• MeSH
• antigen Ki-67 genetika   metabolismus   MeSH
• apoptóza účinky léků   MeSH
• experimentální nádory mléčných žláz farmakoterapie   MeSH
• flavonoidy analýza   farmakologie   MeSH
• fragmentace DNA účinky léků   MeSH
• fytogenní protinádorové látky analýza   farmakologie   MeSH
• kaspasa 3 genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• methylnitrosomočovina toxicita   MeSH
• MFC-7 buňky MeSH
• modely nemocí na zvířatech MeSH
• ovoce chemie   MeSH
• polyfenoly analýza   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protein X asociovaný s bcl-2 genetika   metabolismus   MeSH
• receptor 2 pro vaskulární endoteliální růstový faktor genetika   metabolismus   MeSH
• stilbeny analýza   farmakologie   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-nitrotyrosine MeSH Prohlížeč
• antigen Ki-67 MeSH
• Bax protein, rat MeSH Prohlížeč
• Casp3 protein, rat MeSH Prohlížeč
• Flavin7 MeSH Prohlížeč
• flavonoidy MeSH
• fytogenní protinádorové látky MeSH
• kaspasa 3 MeSH
• Kdr protein, rat MeSH Prohlížeč
• methylnitrosomočovina MeSH
• polyfenoly MeSH
• protein X asociovaný s bcl-2 MeSH
• receptor 2 pro vaskulární endoteliální růstový faktor MeSH
• stilbeny MeSH
• tyrosin MeSH

OBJECTIVES: There has been considerable interest in both clinical and preclinical research about the role of phytochemicals in the reduction of risk for cancer in humans. The aim of this study was to determine the antineoplastic effects of Chlorella pyrenoidosa in experimental breast cancer in vivo and in vitro. METHODS: In this experiment, the antineoplastic effects of C. pyrenoidosa in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Chlorella powder was administered through diet at concentrations of 0.3% and 3%. The experiment was terminated 14 wk after carcinogen administration. At autopsy, mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. In vitro cytotoxicity assay, parameters of apoptosis, and proliferation after chlorella treatment in human breast adenocarcinoma (MCF-7) cells were carried out. RESULTS: Basic parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, proliferation, and angiogenesis), chosen metabolic variables, and side effects after long-term chlorella treatment in animals were assessed. Chlorella at higher concentration suppressed tumor frequency by 61% (P < 0.02) and lengthened tumor latency by 12.5 d (P < 0.02) in comparison with the controls. Immunohistochemical analysis of rat tumor cells showed caspase-7 expression increase by 73.5% (P < 0.001) and vascular endothelial growth factor receptor-2 expression decrease by 19% (P = 0.07) after chlorella treatment. In a parallel in vitro study, chlorella significantly decreased survival of MCF-7 cells in a dose-dependent manner. In chlorella-treated MCF-7 cells, a significant increase in cells having sub-G0/G1 DNA content and significant increase of early apoptotic and late apoptotic/necrotic cells after annexin V/PI staining assay were found. Decreases in mitochondrial membrane potential and increasing reactive oxygen species generation were observed in the chlorella-treated MCF-7 cells. CONCLUSIONS: This study is the first report on the antineoplastic effects of C. pyrenoidosa in experimental breast cancer in vivo and in vitro.

• Klíčová slova
• Angiogenesis, Apoptosis, Cell proliferation, Chlorella, MCF-7, Mammary carcinogenesis, Rat,
• MeSH
• annexin A5 metabolismus   MeSH
• apoptóza MeSH
• Chlorella * MeSH
• dieta MeSH
• fytogenní protinádorové látky farmakologie   terapeutické užití   MeSH
• fytoterapie * MeSH
• kaspasa 7 metabolismus   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• MFC-7 buňky MeSH
• mikrořasy MeSH
• nádory prsu farmakoterapie   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• proliferace buněk MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• annexin A5 MeSH
• fytogenní protinádorové látky MeSH
• kaspasa 7 MeSH
• reaktivní formy kyslíku MeSH
• vascular endothelial growth factor A, rat MeSH Prohlížeč
• vaskulární endoteliální růstový faktor A MeSH

Our previous results indicated significant tumor-suppressive effects of different statins in rat mammary carcinogenesis. The purpose of this experiment was to examine the chemopreventive effects of Pitavastatin alone and in combination with the pineal hormone melatonin in the model of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats. Pitavastatin was administered dietary (10mg/kg) and melatonin in an aqueous solution (20μg/ml). Chemoprevention began 7 days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Compared to controls, Pitavastatin alone reduced average tumor volume by 58% and lengthened latency by 8 days; on the other hand, the drug increased tumor frequency by 23%. Combined administration of Pitavastatin with melatonin decreased tumor frequency by 23%, tumor volume by 44% and lengthened tumor latency by 5.5 days compared to control animals. The analysis of carcinoma cells showed significant increase in caspase-3 expression in both treated groups and a tendency of increased caspase-7 expression after Pitavastatin treatment alone. Significant expression decrease of Ki67 was found in carcinoma cells from both treated groups. Compared to control carcinoma cells, Pitavastatin alone increased VEGF expression by 41%, however melatonin totally reversed its undesirable effect. Pitavastatin combined with melatonin significantly increased femur compact bone thickness in animals. Pitavastatin alone decreased plasma triglycerides and total cholesterol levels, however it significantly increased levels of glucose. In summary, our results show a partial antineoplastic effect of Pitavastatin combined with melatonin in the rat mammary gland carcinoma model.

• Klíčová slova
• Angiogenesis, Apoptosis, Mammary carcinogenesis, Melatonin, Pitavastatin, Proliferation,
• MeSH
• chinoliny terapeutické užití   MeSH
• experimentální nádory mléčných žláz farmakoterapie   MeSH
• krysa rodu Rattus MeSH
• melatonin terapeutické užití   MeSH
• nádory mléčné žlázy u zvířat farmakoterapie   MeSH
• nádory prsu farmakoterapie   MeSH
• protinádorové látky terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinoliny MeSH
• melatonin MeSH
• pitavastatin MeSH Prohlížeč
• protinádorové látky MeSH