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

Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.

• Klíčová slova
• DNA microarray, HMG-CoA reductase inhibitors, atorvastatin, cerivastatin, fluvastatin, pancreatic cancer, pitavastatin, pravastatin, simvastatin, statins,
• MeSH
• buněčná smrt MeSH
• epigeneze genetická MeSH
• kyselina mevalonová metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní farmakoterapie   genetika   metabolismus   patologie   MeSH
• pohyb buněk MeSH
• proliferace buněk MeSH
• protinádorové látky farmakologie   MeSH
• statiny farmakologie   MeSH
• transkriptom účinky léků   MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• kyselina mevalonová MeSH
• protinádorové látky MeSH
• statiny MeSH

Statins, besides being powerful cholesterol-lowering drugs, also exert potent anti-proliferative activities. However, their anti-cancer efficacy differs among the individual statins. Thus, the aim of this study was to identify the biological pathways affected by individual statins in an in vitro model of human pancreatic cancer. The study was performed on a human pancreatic cancer cell line MiaPaCa-2, exposed to all commercially available statins (12 μM, 24 h exposure). DNA microarray analysis was used to determine changes in the gene expression of treated cells. Intracellular concentrations of individual statins were measured by UPLC (ultra performance liquid chromatography)-HRMS (high resolution mass spectrometer). Large differences in the gene transcription profiles of pancreatic cancer cells exposed to various statins were observed; cerivastatin, pitavastatin, and simvastatin being the most efficient modulators of expression of genes involved namely in the mevalonate pathway, cell cycle regulation, DNA replication, apoptosis and cytoskeleton signaling. Marked differences in the intracellular concentrations of individual statins in pancreatic cancer cells were found (>11 times lower concentration of rosuvastatin compared to lovastatin), which may contribute to inter-individual variability in their anti-cancer effects. In conclusion, individual statins exert different gene expression modulating effects in treated pancreatic cancer cells. These effects may be partially caused by large differences in their bioavailability. We report large differences in gene transcription profiles of pancreatic cancer cells exposed to various statins. These data correlate to some extent with the intracellular concentrations of statins, and may explain the inter-individual variability in the anti-cancer effects of statins.

• MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní genetika   metabolismus   patologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• stanovení celkové genové exprese MeSH
• statiny farmakologie   MeSH
• transkriptom účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• statiny MeSH

The treatment of dyslipidemia is beyond doubt one of the cornerstones of cardiovascular prevention. If we want to touch and comment on at least the principal news in this broad field, we must simplify and pay attention to only a few selected areas. The focus of this article is on hypercholesterolemia and the treatment options for elevated low-density lipoprotein (LDL)-cholesterol; it also addresses the questions of low high-density lipoprotein (HDL)-cholesterol levels and the treatment of dyslipidemia of the metabolic syndrome. In particular, statins have had accumulation of new evidence resulting in novel indications and new target groups. Modern, even more potent drugs lowering total and LDL-cholesterol levels are available (new statins, e.g., rosuvastatin, pitavastatin, cholesterol absorption inhibitor ezetimibe) More and more attention of the medical public is being paid to dyslipidemia of the metabolic syndrome (so-called lipid triad), which seems to be the greatest rival of LDL-cholesterol among lipid risk factors for cardiovascular disease. In the treatment of this dyslipidemia especially the nuclear peroxisome proliferator-activated receptor (PPAR) agonists play an important role. In particular fibrates but also glithasones are noteworthy in this respect. There are fewer data for fibrates than for statins, but nevertheless evidence documenting benefit of this therapy is growing. A statin and fibrate combination is a promising future approach not only to the treatment of metabolic syndrome. Moreover, niacin, particularly in combination with a statin, might experience a renaissance. HDL-cholesterol level modification attracts more and more discussions; on the horizon there are new therapies of low HDL, for example, cholesterol-ester transfer protein inhibitors, which have been shown to have a potency for increasing HDL by more than 50%.

• MeSH
• hyperlipidemie farmakoterapie   MeSH
• hypolipidemika terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• hypolipidemika MeSH

BACKGROUND: Statin treatment of hypercholesterolemia is accompanied also with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases. These include Ras proteins, prevalently mutated in pancreatic cancer. In our study, we evaluated the effect of three key intermediates of the mevalonate pathway on GFP-K-Ras protein localization and the gene expression profile in pancreatic cancer cells after exposure to individual statins. METHODS: These effects were tested on MiaPaCa-2 human pancreatic cancer cells carrying a K-Ras activating mutation (G12C) after exposure to individual statins (20 μM). The effect of statins (atorvastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin) and mevalonate intermediates on GFP-K-Ras protein translocation was analyzed using fluorescence microscopy. The changes in gene expression induced in MiaPaCa-2 cells treated with simvastatin, FPP, GGPP, and their combinations with simvastatin were examined by whole genome DNA microarray analysis. RESULTS: All tested statins efficiently inhibited K-Ras protein trafficking from cytoplasm to the cell membrane of the MiaPaCa-2 cells. The inhibitory effect of statins on GFP-K-Ras protein trafficking was partially prevented by addition of any of the mevalonate pathway's intermediates tested. Expressions of genes involved in metabolic and signaling pathways modulated by simvastatin treatment was normalized by the concurrent addition of FPP or GGPP. K-Ras protein trafficking within the pancreatic cancer cells is effectively inhibited by the majority of statins; the inhibition is eliminated by isoprenoid intermediates of the mevalonate pathway. CONCLUSIONS: Our data indicate that the anticancer effects of statins observed in numerous studies to a large extent are mediated through isoprenoid intermediates of the mevalonate pathway, as they influence expression of genes involved in multiple intracellular pathways.

• Klíčová slova
• Farnesyl pyrophosphate, Gene expression, Geranylgeranyl pyrophosphate, HMG-CoA reductase inhibitors, Isoprenoids, K-Ras oncogene, Mevalonate, Pancreatic cancer, Prenylation, Statins,
• MeSH
• anticholesteremika farmakologie   MeSH
• atorvastatin farmakologie   MeSH
• beta-buňky účinky léků   metabolismus   patologie   MeSH
• fluvastatin MeSH
• indoly farmakologie   MeSH
• kyselina mevalonová analogy a deriváty   farmakologie   MeSH
• kyseliny mastné mononenasycené farmakologie   MeSH
• lidé MeSH
• lovastatin farmakologie   MeSH
• mikročipová analýza MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• polyisoprenylfosfáty farmakologie   MeSH
• prenylace proteinů MeSH
• protoonkogenní proteiny p21(ras) genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• rekombinantní fúzní proteiny genetika   metabolismus   MeSH
• seskviterpeny farmakologie   MeSH
• signální transdukce MeSH
• simvastatin farmakologie   MeSH
• stanovení celkové genové exprese MeSH
• transport proteinů účinky léků   MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anticholesteremika MeSH
• atorvastatin MeSH
• farnesyl pyrophosphate MeSH Prohlížeč
• fluvastatin MeSH
• geranylgeranyl pyrophosphate MeSH Prohlížeč
• indoly MeSH
• KRAS protein, human MeSH Prohlížeč
• kyselina mevalonová MeSH
• kyseliny mastné mononenasycené MeSH
• lovastatin MeSH
• polyisoprenylfosfáty MeSH
• protoonkogenní proteiny p21(ras) MeSH
• rekombinantní fúzní proteiny MeSH
• seskviterpeny MeSH
• simvastatin MeSH
• zelené fluorescenční proteiny MeSH