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The effect of flubendazole on temozolomide treatment in glioblastoma cells
Dvořáková, Kateřina ; Skálová, Lenka (advisor) ; Pávek, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Kateřina Dvořáková Supervisor: prof. RNDr. Lenka Skálová, Ph.D. Title of diploma thesis: The effect of flubendazole on temozolomide treatment in glioblastoma cells Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors in adults. Despite significant advances in treatment, GBM remains to have very poor prognosis and median survival of only 12 to 15 months after diagnosis. Standard treatment consists of maximal possible surgical resection followed by chemo-radiotherapy with antitumor drug temozolomide (TMZ), which use is problematic due to fast developing chemoresistance. The aim of this study was to examine the effect of potential anticancer drug, anthelmintic flubendazole (FLU) and effect of FLU in combination with TMZ on GBM cells. For this purpose, two GBM cell lines were used - A172 and T98G. In general FLU reduced cell proliferation more, especially in T98G cells. Moreover, the use of different combinations of TMZ + FLU showed even higher inhibitory effect on the viability of GBM cell lines. The combination of TMZ + FLU reduced the protein level of -tubulin and III-tubulin, simoultaneously interesting changes in STAT3 and EGFR expression, as well as lower...
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Comparison of Iron-chelating Effects of Clinically Used Peroral Iron Chelators and 8-hydroxyquinolines
Zárubová, Pavla ; Mladěnka, Přemysl (advisor) ; Pávek, Petr (referee)
in English Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Candidate: Pavla Zárubová Consultant: Přemysl Mladěnka, Ph.D. Name of thesis: Comparison of iron-chelating effects of clinically used peroral iron chelators and 8-hydroxyquinolines Iron is an essentials element, which takes part in many vital processes. However, excessive iron can be toxic for the organism by catalyzing production of free radicals. Long-term administration of blood transfusions in the therapy of various anaemias is the most common cause of iron overload. Each transfuzion represents an intake of 200-250 mg iron in the organism, which due to low daily elimination (only 1-2 mg) leads to iron overload. As a result, complications like cardiovascular impairment or liver fibrosis can emerge. The risk of these severe complications can be reduced by administration of iron chelators. Deferoxamine has been traditionally used for the chelation therapy of chronic iron overload, but to his disadvantages belong frequent parenteral applications. In these days we can also use modern orally acive chelators (deferipron, deferoxamin). Furthermore, there is a wide range of potentially new indications (inflammation, tumor, cardiovascular and neurodegenerative diseases). In all these...
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Interaction of selected anthocyanidins with farnesoid X receptor
Jeřábková, Jana ; Pávek, Petr (advisor) ; Martin, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jana Jeřábková Supervisor: Doc. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Interaction of selected anthocyanidins with farnesoid X receptor Human farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that act as ligand-activated transcription factors. FXR binds to specific regulatory DNA regions and induces expression of many target genes. These regulated genes are involved in bile acid metabolism and transport, maintaining blood lipids, liporoteins and glucose homeostasis and also contribute to maintain intestinal bacterial balance, hepatoprotection and liver regeneration. The interest of recent studies is to test the range of FXR ligands for treatment and prevention of many diseases such as cholestais, cholesterol gallstone disease, steato-hepatitis, dyslipidemia, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, liver cancer and other forms of cancer such as breast cancer. In this experimental diploma thesis we are focused on testing of potencial ligands of human farnesoid X receptor from the group of natural plant pigments anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin) using the human hepatoma cell line...
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The role of ABC transporter in clinical practise
Tornová, Petra ; Pávek, Petr (advisor) ; Čečková, Martina (referee)
The role of ABC transporters in clinical practice ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. There are seven subfamilies classified as ABC transporters (ABCA through ABCG) that are expressed in both normal and malignant cells. They are involved in the transport of many substances, including the excretion of toxins from the liver, kidneys, and gastrointestinal tract, and they limit permeation of toxins to vital structures, such as the brain, placenta, and testis. The best-characterized transporter protein is MDR1/P-glycoprotein, and a number of clinical investigations have suggested that its intrinsic or acquired overexpression resulted in a poor clinical outcome of chemotherapy. Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane. Various types of compounds and techniques for the reversal of ABC transporters mediated MDR have been developed, and efforts have concentrated on the inhibition of function and suppression of expression. Increased drug accumulation and...
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Implication of the Gabaergic System in Altered Responses to Stress Associated to Maternal Separation
Martišová, Eva ; Pávek, Petr (advisor) ; Štaud, František (referee)
in English language - diploma thesis Implication of the Gabaergic System in Altered Responses to Stress Associated to Maternal Separation Eva Martišová This diploma thesis studied whether the GABA system alters responses to stress induced by maternal separation in rats. The aim was to examine the influence of maternal separation on GABA neurotransmission, in particularly, the biochemical markers of the system (levels of the neurotransmitter GABA, GABA A receptor expression), and to study of gender-related differences in behavioral and neurochemical processes in rats induced by maternal separation. In order to pursue the objectives, it was necessary to develop a model of maternal separation in rats. Rat pups were separated from their mother for three hours a day from postnatal day 2 to postnatal day 21 (in the postnatal period, when the reduced ability to respond to stressful stimuli). At postnatal day 23 pups were removed from mothers, divided into groups of the same sex. Then pups were without significant manipulation left to grow into adulthood. After reaching adulthood (> 60 days) rats were divided into two groups. The first group was killed by decapitation and different brain regions (anterior and temporal cortex, corpus striatum and hippocampus) were used to determine the levels of GABA using...
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The Repair of Oxidative DNA Damage in the Chinese Hamster Cell Line Deficient in Nucleotide Excision Repair
Strejčková, Lada ; Trejtnar, František (advisor) ; Pávek, Petr (referee)
The repair of oxidative DNA damage in the Chinese hamster cell line deficient in nucleotide excision repair Abstract The aim of our work was to specify DNA oxidative damage repair in the Chinese hamster ovary cell line. Comet assay was used to detect the damage consequences - DNA breaks. We were capable of achieving high method sensitivity due to application of specific endonucleases and specific inhibitors of excision repair - inhibitor of poly(ADP- ribose)polymerase PARP 3-aminobenzamide (3-AB) and cytosine arabinoside with hydroxyurea (AraC/HU). PARP-1 is an important factor in the base excision repair (BER) process. PARP-1 deficient cells show recovery impairment both in LP-BER and SP-BER way. AraC/HU is known as the long-patch excision repair inhibitor. The results of our experiments showed the inhibiting effect of 3-AB on the repair of hydrogen peroxide-induced DNA damage. But in the same setting the AraC/HU effect on repair was not observed. To make the value of experimental results more significant and clear, we decided for additional experiments with monofunctional alkylating agent methyl methanesulfonate (MMS). Damage caused by MMS showed slower repair both when 3-AB or AraC/HU were present during the repair period. Based on all available results we suppose that the MMS and also hydrogen peroxide...
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Interactions of resveratrol derivatives with PXR receptor
Marešová, Veronika ; Pávek, Petr (advisor) ; Trejtnar, František (referee)
Charles University in Prague Department of Pharmacology & Toxicology Student: Supervisor: Prof Title of diploma thesis: Interactions of resveratrol derivatives with PXR receptor Derivatives of resveratrol belong between natural substances contained mainly in red wine and grapefruit. These compounds with stilbene-like structure show antioxidant activity. Pregnane X receptor (PXR) regulates expression of the most important biotransformation enzymes in human liver and intestine including cytochrome P450 3A4 (CYP3A4). Interaction of resveratrol and PXR have already been studied, but published data are contradictory. In my diploma thesis, I studied interaction of resveratrol and its derivatives with PXR. For this purpose, gene reporter assay with quantitative real-time polymerase chain reaction (qRT-PCR) was introduced. It was not possible to conduct experiments in standard way because both resveratrol and its derivatives inhibit lusiferase activities. I studied also effects of resveratrol and its derivatives on expression of CYP3A4 mRNA on differentiated HepaRG cell line. New method gene reporter method with qRT-PCR detection of luciferase was established on hepatoma cell line HepG2 transfected with CYP3A4 reporter construct. Concertation dependent effects of resveratrol and its derivatives were...
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