Statins (inhibitors of HMG-CoA reductase) belong to widely used drugs in human medicine due to their efficient cholesterol lowering effects. Besides this obvious action, statins exert a number of other pleitropic biological effetcs, which contribute to prevention of many diseases, in particular in cardiovascular medicine, transplantology, nefrology, and also possible protective effects in cancer diseases are increasingly discussed. Potential anticancer effects of statins are still subject of discussion, because some clinical studies are controversial. The main reason may the substantial heterogenity of anticancer effects of statins, which, however, differ substantially in their pharmacokinetic and pharmacodynamic properties. Thus, investigation of all these aspects is the major subject of proposed grant project.

Statiny (inhibitory HMG-CoA reduktázy) patří mezi široce používané léky v humánní medicíně pro jejich velmi účinné hypocholesterolemické účinky. Kromě těchto hypolipidemických účinků však statiny mají řadu dalších pleitropních biologických efektů, které hrají významnou roli v prevenci progrese některých onemocnění, zejména v kardiovaskulární medicíně, v transplantologii, nefrologii, uvažuje se také o protektivních účincích u nádorových onemocnění. Potenciální protinádorové účinky statinů jsou však stále předmětem diskuse, neboť některé klinické práce tyto účinky zpochybňují. Hlavním důvodem může být značná heterogenita protinádorových účinků jednotlivých statinů, které se významně liší svými farmakokinetickými a farmakodynamickými vlastnostmi. Studium všech těchto aspektů je předmětem předkládaného grantového projektu.

• MeSH
• adjuvantní chemoterapie MeSH
• genetická pleiotropie MeSH
• hydroxymethylglutaryl-CoA-reduktasy MeSH
• hypercholesterolemie farmakoterapie   MeSH
• inhibitory angiogeneze MeSH
• nádory slinivky břišní farmakoterapie   MeSH
• statiny terapeutické užití   MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

BACKGROUND: Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway. METHODS: In vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2. RESULTS: While simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01). CONCLUSIONS: Anti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive oxygen species-induced cell death, cerivastatin targets Ras protein trafficking and affects markers of invasiveness.

• MeSH
• apoptóza účinky léků   MeSH
• hemoxygenasa-1 genetika   metabolismus   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• nádorové buňky kultivované MeSH
• nádory slinivky břišní farmakoterapie   metabolismus   patologie   MeSH
• pankreas metabolismus   MeSH
• pohyb buněk účinky léků   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk účinky léků   MeSH
• ras proteiny genetika   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce MeSH
• statiny farmakologie   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Statins (HMG-CoA reductase inhibitors) represent a major class of compounds for the treatment of hypercholesterolemia due to their ability to inhibit de novo cholesterol synthesis. In addition to their hypolipidemic effects, chemoprotective properties have been attributed to statins as well. These effects involve multiple mechanisms, which, however, are not known in detail. The aim of our study was to assess in non-malignant as well as cancer cells the impact of simvastatin on the amount of cytosolic lipid droplets (LDs) implicated in many biological processes including proliferation, inflammation, carcinogenesis, apoptosis, necrosis or growth arrest. METHODS: Human embryonic kidney cells HEK-293T and human pancreatic cancer cells MiaPaCa-2 were treated with simvastatin (6 and 12 muM) for 24 and 48 hours respectively. Neutral lipid probe Nile Red was used for detection of LDs by fluorescence microscopy. Cellular cholesterol content was determined by HPLC. Changes in expression of genes related to lipid metabolism in simvastatin-treated MiaPaCa-2 cells were examined by DNA microarray analysis. Validation of gene expression changes was performed using quantitative RT-PCR. RESULTS: The treatment of the cells with simvastatin increased their intracellular content of LDs in both non-malignant as well as cancer cells, partially due to the uptake of cholesterol and triacylglyceroles from medium; but in particular, due to enhanced synthesis of triacylglyceroles as proved by significant overexpression of genes related to de novo synthesis of triacylglyceroles and phospholipids. In addition, simvastatin also markedly influenced expression of genes directly affecting cell proliferation and signaling. CONCLUSIONS: Simvastatin treatment led to accumulation of cytosolic LDs within the examined cells, a phenomenon which might contribute to the antiproliferative effects of statins.

• MeSH
• cholesterol metabolismus   MeSH
• HEK293 buňky účinky léků   MeSH
• lidé MeSH
• lipidová tělíska * metabolismus   účinky léků   MeSH
• metabolismus lipidů genetika   účinky léků   MeSH
• nádorové buněčné linie účinky léků   MeSH
• nádory slinivky břišní * farmakoterapie   metabolismus   MeSH
• proliferace buněk genetika   účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• simvastatin * farmakologie   MeSH
• statiny * farmakologie   MeSH
• Check Tag
• lidé MeSH

Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM.

• MeSH
• antigen CD24 metabolismus   MeSH
• antitumorózní látky farmakologie   MeSH
• buněčná adheze účinky léků   MeSH
• buněčné sféroidy účinky léků   patologie   MeSH
• fenotyp MeSH
• genový knockdown MeSH
• inhibiční koncentrace 50 MeSH
• invazivní růst nádoru MeSH
• lidé MeSH
• mezoteliom metabolismus   patologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• myši nahé MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• nádory plic metabolismus   patologie   MeSH
• progrese nemoci MeSH
• proliferace buněk účinky léků   MeSH
• tokoferoly farmakologie   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH