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Inhibitors of human enzyme akr1C3 of plant origin
Lojdová, Kateřina ; Novotná, Eva (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Kateřina Lojdová Supervisor: RNDr. Eva Novotná, Ph.D. Consultant: RNDr. Lucie Zemanová, Ph.D. Title of thesis: Inhibitors of human enzyme AKR1C3 of plant origin Enzyme AKR1C3 is a part of large superfamily of aldo-keto reductases. It is a hydroxysteriod dehydrogenase, in human body it participates among others in steroid hormone metabolism but also in activation and deactivation of some drugs. Increased expression of this enzyme is linked to higher aggressivity of some neoplastic diseases and poor prognosis of the treatment, e.g. prostate cancer. This makes AKR1C3 an interesting target for farmaceutical and medical research. Discovery of strong and selective AKR1C3 inhibitor is the first step in finding a drug, that could affect tumor metabolism and restore its sensitivity to treatment. There were 32 naturally occuring compounds from flavonoid and alkaloid groups tested in this study. Its goal was to determine inhibiton efficacy of selected compounds to enzyme AKR1C3. Reduction of a potential anticancer drug oracin to dihydrooracin was used for the measurement, the results were evaluated using an HPLC analysis. IC50 was determined for compounds with significant inhibitory effect.
Study of protein-protein interaction of DHRS7 enzyme by pull-down assay
Hermanová, Kateřina ; Novotná, Eva (advisor) ; Matoušková, Petra (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Biochemical Sciences Candidate: Kateřina Káchová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Study of protein-protein interaction of DHRS7 enzyme by pull-down assay Dehydrogenase/reductase (SDR family) member 7 (DHRS7) is one of the less studied enzymes of SDR superfamily. It has been proven that this enzyme is in vitro involved in reductive metabolism of various compounds, such as steroids, retinoids and xenobiotics. Recently results pointing out to possible role of this enzyme in the pathogenesis of prostate cancer or other diseases has been published. It would be suitable to better characterize this enzyme to clarifying its patho/physiological role in the organism. Because protein-protein interactions seem to be important for the function of proteins, the aim of this study was to identify interaction partners of the DHRS7, and thus contribute to the improvement of understanding of this enzyme. For our experiments, pull-down assay, in vitro method was utilized. The first step was immobilization of DHRS7 enzyme (bait protein) to suitable carrier (His Mag Sepharose Ni particles and nonmagnetic Protino Ni-IDA particles). Subsequently, the carrier with immobilized DHRS7 was incubated with the lysate of Hep G2...
Effect of selected cytostatics for the treatment of leukemia on the activity of human carbonyl reducing enzymes
Šmídlová, Monika ; Novotná, Eva (advisor) ; Wsól, Vladimír (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical sciences Candidate: Bc. Monika Šmídlová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Effect of selected cytostatics for the treatment of leukemia on the activity of human carbonyl reducing enzymes Key words: reductases, leukemia, cytostatics, inhibition Anthracycline antibiotics, especially daunorubicin, are widely used for the treatment of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Although the efficacy of these drugs is high, treatment is still limited due to cardiotoxicity and tumor cell resistance to anthracyclines. Mechanisms that contribute to the formation of anthracycline resistance include metabolic biotransformation (reduction) to less efficient secondary alcohols. The reduction is calatyzed by carbonyl reducing enzymes belonging to aldo-keto reductase (AKR) and short chain dehydrogenase/reductase (SDR) superfamilies. The discovery of AKR and SDR inhibitors could help to overcome anthracycline resistance and also reduce cardiotoxicity caused by these drugs. The aim of the diploma thesis was to find out whether all-trans-retinoic acid, cyclophosphamide, cytarabine, cladribine and prednisolone are able to inhibit anthracycline reductases AKR1A1, AKR1B10, AKR1C3, AKR7A2...
Study of resistance in cancer therapy - protein kinase inhibitors influence on activity of selected human reductases II.
Flaxová, Michaela ; Wsól, Vladimír (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Michaela Flaxová Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: Study of resistance in cancer therapy - protein kinase inhibitors influence on activity of selected human reductases II. Nowadays cancerous diseases are significant problem, and the incidence is still increasing. Anthracycline antibiotics are important in therapy of cancerous diseases, unfortunately, they have serious side effects and drug resistance is often obstacle for the effective treatment. The origin of cardiotoxicity is still not clear, older theories were based on formation of reactive oxygen species (ROS). Nevertheless, newer theories confirm that anthracyclines or their metabolites influence complicated cell pathways. The enzymes, which metabolize anthracyclines, specifically daunorubicin, were the subject of this work. The carbonyl reducing enzymes are NADP(H)-dependent oxidoreductases, which are able to catalyse reduction of aldehydes and ketones to primary and secondary metabolites, daunorubicin is transformed to daunorubicinol directly by this way. Therefore we are most interested in enzymes from aldo-keto reductase family and short-chain dehydrogenases (SDR), namely AKR1C3 and CBR1. Many enzymes...
Study on impact of selected protein kinase inhibitors on drug resistance mediated by cytochromes P450
Janoušková, Adéla ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Janoušková Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study on impact of selected protein kinase inhibitors on drug resistance mediated by cytochromes P450 Pharmacokinetic drug resistance often leads to failure of an anticancer therapy. One of the mechanisms is increased efflux of drugs from tumour cells, whereas some studies suggest that increased drug conversion to an inactive metabolite might be another contributing mechanism. The aim of this work was to define the possible role of CYP3A4 and CYP2C8 enzymes in the phenomenon of pharmacokinetic resistance and to investigate the possibility of its modulation by new targeted drugs. In the first part, we used the MTT proliferation method together with HepG2 cells stably transduced with particular human enzymes and demonstrated significant involvement of CYP3A4 in docetaxel resistance. In the following part, we examined the inhibitory effects of four selected tyrosine kinase inhibitors on the CYP3A4 activity in intact cells using a commercial kit. Cobimetinib and dabrafenib showed significant inhibitory activity, while osimertinib and brivanib did not. In the final part, we demonstrated the ability of the first two...
Natural compounds isolated from plants at the Faculty of Pharmacy in Hradec Králové as potential inhibitors of aldo-ketoreductase 1A1 (AKR1A1)
Karásková, Jitka ; Novotná, Eva (advisor) ; Raisová Stuchlíková, Lucie (referee)
Charles Universtity Pharmaceutical Faculty in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Jitka Karásková Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Natural compounds isolated from plants at the Faculty of Pharmacy in Hradec Králové as potential inhibitors of aldo-ketoreductase 1A1 (AKR1A1) Aldo-keto reductase 1A1 is an enzyme belonging to the aldo-keto reductase superfamily. It is a monomeric, cytosolic enzyme that is able to reduce carbonyl groups within a wide range of substrates. The enzyme is expressed in almost every tissue in the body, most represented in hepatocytes, renal cells and salivary glands, where it contributes to the reduction of endogenous substrates and the first phase of biotransformation of xenobiotics. AKR1A1 catalyzes NADPH-dependent reduction of aldehydes and ketones to their corresponding primary and secondary alcohols. Enzyme substrates include, for example, mevalonate; anthracycline antibiotics doxorubicin or daunorubicin; some pro-carcinogens that are activated by the reaction into carcinogens, such as: trans- dihydrodiol metabolites of polycyclic aromatic hydrocarbons. Generally, it is involved in the metabolism of lipids and carbohydrates that contain an aldehyde function. The increased expression and activity of AKR1A1 has been...
Interaction of natural substances with human aldo-keto reductase 7A2 and other important carbonyl reducing enzymes
Homerová, Andrea ; Novotná, Eva (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Andrea Homerová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Interaction of natural substances with human aldo-keto reductase 7A2 and other important carbonyl reducing enzymes Reduction of carbonyl group is one of the phase I metabolism reactions, which is responsible for production of more polar metabolites, enables conjugation in process of biotransformation, excretion of the molecule and it also causes decrease in reactivity and biological activity of the molecule. Endogenous as well as exogenous compounds undergo this reaction and carbonyl reducing enzymes are the ones which possess this reducing activity. Based on the structure, we can divide the enzymes into several groups: short-chain dehydrogenases/reductases, medium-chain dehydrogenases/reductases, aldo-keto reductases and quinone reductases. Inhibition of carbonyl reducing enzymes appears to be a promising aim of research. It is important to take into consideration that by inhibiting carbonyl reducing enzymes it is possible to reduce production of less active, but more toxic metabolites, for example in anthracycline chemoteraputics daunorubicin and doxorubicin and that can lead to change in therapy of cancer. This study...
Study of the cytotoxicity of selected chemotherapeutics for the treatment of leukemia in human tumor cell lines.
Štorkánová, Jesika ; Novotná, Eva (advisor) ; Jansová, Hana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Jesika Štorkánová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Study of the cytotoxicity of selected chemotherapeutics for the treatment of leukemia in human tumor cell lines Leukemia represents a diverse group of malignant diseases with a hematopoietic disorder with different prognoses. As the incidence of patients with leukemia is increasing, is an effort to establish the treatment that will lead to successful therapy. One of the basic approaches to the treatment of leukemias is chemotherapy. Today it is known that the effectiveness of chemotherapy is influenced by a number of factors which can significantly affect the treatment strategy and thus decide on the outcome of the treatment itself. An important approach in chemotherapy is the selection of cytostatics with maximum efficacy for oncological disease and elimination cytostatics to which the cells are resistant based on the findings in in vitro conditions. The aim of this diploma thesis was to determine the inhibitory effects of in vitro selected chemotherapeutics in cell tumor lines. For determine the inhibitory effect, HCT116, HepG2 and HL-60 cell lines were selected using a colorimetric method based on the...
Characterization of flubendazol reduction in human in vitro
Štěpánková, Jana ; Szotáková, Barbora (advisor) ; Novotná, Eva (referee)
ASBSTRACT Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Jana Štěpánková Supervisor: Prof. Ing. Barbora Szotáková, Ph.D. Title of Thesis: Characterization of flubendazol reduction in human in vitro Flubendazole (FLU) is an anthelmintic of the benzimidazole type used as a treatment or prophylaxis of helminthoses in livestock and wild animals. FLU is also registered for the treatment of parasitic diseases caused by intestinal nematodes in humans. Its mechanism of action lies in its specific binding to tubulin, which disrupts the structure and function of microtubules for the therapy of parasitosis in humans. The advantage of this drug is also the low systemic toxicity. That is why the anticancer activity of FLU is now under study. The aim of this rigorous work was to characterize the reduction of FLU in human liver subcellular fractions as this information is still lacking in available literature. Stereospecificity, subcellular localization, preference of coenzymes, enzyme kinetics of FLU reduction, and activity of enzymes involved in FLU reduction were studied in this project. Measurement results have shown that FLU is predominantly reduced in cytosol and nicotinamide adenine dinucleotide phosphate reduced (NADPH) coenzyme is preferred. FLU...

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