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The use of selected inhibitors to overcome anthracycline resistance in cancer therapy (in vitro study).
Tučková, Kateřina ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Kateřina Tučková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Consultant: Mgr. Lenka Laštovičková, Ph.D. Title of diploma thesis: The use of selected inhibitors to overcome anthracycline resistance in cancer therapy (in vitro study) Resistance to chemotherapy is a severe problem in treating cancer patients, significantly reducing their chances of recovery. The increased expression of carbonyl reductases in tumour cells is one of the leading causes of the resistance. These enzymes can reduce anthracycline-based chemotherapy drugs to their less effective derivatives and thus significantly reduce their efficiency. Therefore, the inhibitors of carbonyl reductases could increase the effectiveness of anthracycline-based chemotherapy. The goal is to find an inhibitor with high inhibitory activity and low side effects. This thesis tested inhibitors asciminib, tucatinib, sotorasib, and umbralisib hydrochloride against carbonyl reductases from the aldo-keto reductase superfamily (AKR1C3, 1A1, 1B1, 1B10) and short-chain dehydrogenases/reductases superfamily (CBR1), using chemotherapy drug daunorubicin. The most significant inhibitory potential was observed between asciminib and the enzyme AKR1C3,...
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The effect of the tyrosine kinase inhibitor tirabrutinib on anthracycline resistance in a tumor cell line.
Lebeková, Nikola ; Wsól, Vladimír (advisor) ; Matoušková, Petra (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Nikola Lebeková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The effect of tyrosine kinase inhibitor tirabrutinib on anthracycline resistance in a cancer cell line Malignancies represent a broad spectrum of heterogeneous diseases caused by genetic and epigenetic alterations that negatively affect various human tissues, contributing to the development of malignancy. Chemotherapy is considered one of the main pillars in the treatment of malignant diseases. Anthracycline chemotherapeutics are widely used drugs in these indications. However, adverse effects resulting from their mechanism of action are a major obstacle. The role in the development of cardiotoxicity, as one of the adverse effects of therapy, is played by carbonyl reducing enzymes that produce toxic reduced metabolites by conferring metabolic reduction of anthracyclines. At the same time, these metabolites show significantly lower cytotoxic activity, thus contributing to the formation and further development of resistance, another severe obstacle in clinical practice. This thesis aimed to investigate the inhibitory effect of a specific tyrosine kinase inhibitor tirabrutinib at the cellular level. The...
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The effect of zanubrutinib on tumor cell resistance to daunorubicin due to carbonyl reducing enzymes.
Havlíčková, Lucie ; Wsól, Vladimír (advisor) ; Matoušková, Petra (referee)
5 Abstract Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Lucie Havlíčková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The effect of zanubrutinib on tumor cell resistance to daunorubicin due to carbonyl reducing enzymes Anthracycline antibiotics (ANT) are considered the first-line medication for oncologic diseases, including acute myeloid leukemia. Daunorubicin (DAUN) with a carbonyl group in position 13 is often used in chemotherapeutic treatments. Nicotinamidadenindinucleotid-phosphate dependent carbonyl reducing enzymes (CRE) create its hydroxyl metabolite daunorubicinol (DAUN-ol), which demonstrates higher toxicity on myocardial tissue and lower cytotoxicity on cancer cells, which acquire tolerance towards its effects. Overexpression of enzymes catalyzing the conversion of effective antineoplastic DAUN causes the gradual development of resistance to administered ANT. For this reason, the new pharmacotherapeutic options for preventing this process are being searched for to maintain the drug in the target cell as long as possible. One option is to use inhibitors, which lower enzymatic activity CRE and prevent unfavorable DAUN metabolism on cardiotoxic and ineffective DAUN-ol. This diploma thesis aimed to study the...
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Isocitrate dehydrogenase 2 inhibitor enasidenib synergizes daunorubicin cytotoxicity by targeting aldo-keto reductase 1C3.
Haddad, Andro ; Wsól, Vladimír (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Andro Haddad Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Consultant: Anselm Morell García, Ph.D. Title of diploma thesis: ISOCITRATE DEHYDROGENASE 2 INHIBITOR ENASIDENIB SYNERGIZES DAUNORUBICIN CYTOTOXICITY BY TARGETING ALDO-KETO REDUCTASE 1C3 Treatment with anthracyclines is crucial in treating several oncologic disorders. However, several molecular mechanisms hinder the effectivity of anthracyclines, which is a significant obstacle in cancer therapy. Carbonyl reducing enzymes (CREs), a type of NAD(P)H-dependent oxidoreductase, contribute to anthracycline resistance by reducing these drugs to fewer active alcohols. These enzymes also play a role in the proliferation and differentiation of cancer cells, leading to increased tumour aggressiveness. Therefore, targeting these enzymes is essential for effective anticancer therapy. This study aimed to uncover the potential off-targets of the isocitrate dehydrogenase (IDH) inhibitor enasidenib (ENA) that could counteract the resistance to anthracycline, specifically in relation to the detoxification role of CREs. For this, we screened the ability of ENA to inhibit different recombinant CREs that can reduce daunorubicin (Daun) to daunorubicinol...
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The use of selected inhibitors to overcome anthracycline resistance in cancer therapy (in vitro study).
Tučková, Kateřina ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Kateřina Tučková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Consultant: Mgr. Lenka Laštovičková, Ph.D. Title of diploma thesis: The use of selected inhibitors to overcome anthracycline resistance in cancer therapy (in vitro study) Resistance to chemotherapy is a severe problem in treating cancer patients, significantly reducing their chances of recovery. The increased expression of carbonyl reductases in tumour cells is one of the leading causes of the resistance. These enzymes can reduce anthracycline-based chemotherapy drugs to their less effective derivatives and thus significantly reduce their efficiency. Therefore, the inhibitors of carbonyl reductases could increase the effectiveness of anthracycline-based chemotherapy. The goal is to find an inhibitor with high inhibitory activity and low side effects. This thesis tested inhibitors asciminib, tucatinib, sotorasib, and umbralisib hydrochloride against carbonyl reductases from the aldo-keto reductase superfamily (AKR1C3, 1A1, 1B1, 1B10) and short-chain dehydrogenases/reductases superfamily (CBR1), using chemotherapy drug daunorubicin. The most significant inhibitory potential was observed between asciminib and the enzyme AKR1C3,...
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The effect of zanubrutinib on tumor cell resistance to daunorubicin due to carbonyl reducing enzymes.
Havlíčková, Lucie ; Wsól, Vladimír (advisor) ; Matoušková, Petra (referee)
5 Abstract Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Lucie Havlíčková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The effect of zanubrutinib on tumor cell resistance to daunorubicin due to carbonyl reducing enzymes Anthracycline antibiotics (ANT) are considered the first-line medication for oncologic diseases, including acute myeloid leukemia. Daunorubicin (DAUN) with a carbonyl group in position 13 is often used in chemotherapeutic treatments. Nicotinamidadenindinucleotid-phosphate dependent carbonyl reducing enzymes (CRE) create its hydroxyl metabolite daunorubicinol (DAUN-ol), which demonstrates higher toxicity on myocardial tissue and lower cytotoxicity on cancer cells, which acquire tolerance towards its effects. Overexpression of enzymes catalyzing the conversion of effective antineoplastic DAUN causes the gradual development of resistance to administered ANT. For this reason, the new pharmacotherapeutic options for preventing this process are being searched for to maintain the drug in the target cell as long as possible. One option is to use inhibitors, which lower enzymatic activity CRE and prevent unfavorable DAUN metabolism on cardiotoxic and ineffective DAUN-ol. This diploma thesis aimed to study the...
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The influence of branebrutinib on the activity of selected reductases from AKR and SDR superfamilies.
Fiklíková, Barbora ; Wsól, Vladimír (advisor) ; Matoušková, Petra (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Barbora Fiklíková Supervisor: Vladimír Wsól, Ph.D. Title of diploma thesis: The influence of branebrutinib on the activity of selected reductases from AKR and SDR superfamilies Acute myeloid leukaemia (AML), along with other cancer diseases, is a widespread health problem not just in the Czech Republic but in the entire world. There is no reliable cure, and millions of people die of cancer every year. Anthracycline antibiotics (ANT) such as daunorubicin have been used as the cure for many years in combination with other cytostatics. However, even these drugs have their issues. One of the problems is toxicity for the healthy cells (especially cardiomyocytes) caused by the inhibition of topoisomerase 2β and by the reactive oxygen species (ROS) formation. The other problem is the increasing resistance of the ANT to cancer cells. ANTs are metabolized by carbonyl reducing enzymes to appropriate alcohols with lower effects against cancer cells and more severe toxicity for the heart cells. The inhibition of these enzymes could be used to achieve better therapeutic results. One of the potential inhibitors could be branebrutinib (BRA). It inhibits Bruton tyrosine kinase and is used to cure...
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Investigation of sugar modified pyrimidine nucleosides as potential inhibitors of Thymidine (TP) and Uridine (UP) phosphorylasis
Růžičková, Markéta ; Wsól, Vladimír (advisor) ; Boušová, Iva (referee)
1 Abstract of the thesis RŮŽIČKOVÁ M.; INVESTIGATION OF SUGAR MODIFIED PYRIMIDINE NUCLEOSIDES AS POTENTIAL INHIBITORS OF THYMIDINE (TP) AND URIDINE (UP) PHOSPHORYLASE Key words: uridine phosphorylase, thymidine phosphorylase, nucleoside, inhibitor, anticancer chemotherapy, substrate specifity The work deals with the investigation of novel potential inhibitors of recombinant thymidine and uridine phosphorylases from E. coli and Salmonella typhimurium. The main goals of this study are the determination of kinetic parameters for natural substrates (thymidine and uridine) for recombinant TP and UP, assessment of the role of phosphate anion in the enzymatic transformations and search for new inhibitors of TP and UP. Study of UP and TP substrate specifity and activity under the various reaction conditions is desired to obtain better view to their functions and to design novel structures of potencial inhibitors. The determination of the Michaelis constant KM and reaction rate Vmax was performed at the spectrophotometer Varian Cary-300 Bio. The representation of obtained kinetic data we used the Lineweawer-Burk plot. The next point of my work was the determination of the enzymatic activity and their substrate specifity for some pyrimidine analogues by HPLC analysis of reaction mixtures. Tested compounds...
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Studies of the interaction between human AQP5 and PIP
Nešverová, Veronika ; Wsól, Vladimír (advisor) ; Zemanová, Lucie (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences University of Gothenburg Faculty of Science Department of Chemistry and Molecular Biology Candidate: Veronika Nešverová Supervisor: Vladimír Wsól Title of diploma thesis: Studies of the interaction between human AQP5 and PIP Aquaporin 5 is a membrane canal which maintains water balance mainly in lacrimal and salivary glands. A defect in this protein's trafficking from cytoplasm to cytoplasmic membrane is thought to play a role in development of Sjögren's syndrome - a chronic autoimmune disease. Prolactin-inducible protein is a cytoplasmic protein which was found to be contributing to this disease's pathogenesis. This project was aimed to study the proposed interaction between aquaporin 5 and prolactin-inducible protein. Both recombinant proteins were overexpressed in the yeast Pichia pastoris and purified using low-pressure column chromatography on an ÄKTA purification system. Glycosylation of prolactin-inducible protein was confirmed using specific glycoprotein staining. Two coelution tries were run on a HisTrap column. The fractions eluted from the second try were analysed by mass spectrometry. However results did not confirm any interaction. Further investigation is needed for the complete...
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Role of systemic inflammation in Parkinson's disease
Veselá, Karolína ; Wsól, Vladimír (advisor) ; Zemanová, Lucie (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences University of Seville, Faculty of Pharmacy Department of Biochemistry and Molecular Biology Candidate: Karolína Veselá Supervisors: Prof. Dr. José Luis Venero Recio, Prof. Ing. Vladimír Wsól, Ph.D Title of diploma thesis: Role of Systemic Inflammation in Parkinson's Disease. Parkinson's disease (PD) is the second most common ageing-related neurodegenerative disorder after Alzheimer's disease and the prevalence in population is increasing. The characteristic movement disorder is caused by selective dopaminergic neurons loss, while the mechanism of this neurodegeneration is not well understood. Increasing evidence points out the key role of vicious cycle of microglial overactivation and oxidative stress, while the questions "where it begins" and "how to stop it" remain without clear answers. This thesis investigates implication of peripheral inflammation as a deteriorating circumstance and possible inductor of brain inflammation and progressive dopaminergic neurodegeneration. We use mice model of Parkinson's disease employing single intraperitoneal injection of toxin N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) that induces specific degeneration of DA neurons and in contrast to other animal...
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