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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...
The influence of midostaurin, vistusertib and talazoparib inhibition on the activity of selected reductases from AKR and SDR superfamilies
Milan, Jaroslav ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical sciences Candidate: Bc. Jaroslav Milan Supervisor: prof. Ing. Vladimír Wsól, PhD. Consultant: RNDr. Eva Novotná, PhD. Title of diploma thesis: The influence of midostaurin, vistusertib and talazoparib inhibition on the activity of selected reductases from AKR and SDR superfamilies. Key words: reductase, AKR, inhibitors, midostaurin, vistusertib, talazoparib, anthracyclines, KG1a Multi drug resistance is for a lot of years still a big problem in therapy of cancer. Anthracycline antibiotics are highly efficient for treating cancers but multi drug resistance and severe side effects sometimes restrain the use of them and lead therapy to fail. One of the worst adverse effect is a cardiotoxicity. By older studies, the mechanism of a cardiotoxicity was because of formation of reactive oxygen species (ROS). Many times, the negative effects of ROS on cardiac muscle cells was confirmed but nowadays the evidence opens some other and more complex mechanisms of its damage. The main point of this work was examination of enzymes which metabolize anthracyclines, mainly daunorubicin. Metabolites which are formed are less potent than parent drug and they have bigger toxicity. This can have an impact on therapy and can cause a...
The influence of bosutinib, neratinib and ibrutinib inhibition on the activity of selected reductases from AKR and SDR superfamilies
Hudáčová, Lenka ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Lenka Hudáčová Supervisor: Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The influence of bosutinib, neratinib and ibrutinib inhibition on the activity of selected reductases from AKR and SDR superfamilies Anthracycline antibiotics (ANTs) are antineoplastic drugs. Daunorubicin (DAUN) is used in the treatment of acute leukaemia. Enzymes from aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies mediate the reduction of DAUN to its C-13 alcohol metabolite daunorubicinol (DAUNOL), which is more cardiotoxic, less antineoplastic and is causing anthracycline resistance. In my diploma thesis, I examined the inhibitory effect of bosutnib, neratinib and imatinib on the activity of enzymes from the SDR and AKR superfamilies. The specific enzyme activity and inhibitory effect were estimated on the base of in vitro enzymatic production of DAUNOL by the ultra-high-performance liquid chromatography (UHPLC) system. MTT assay was used to measure DAUN and ibrutinib cytotoxicity effect on HCT116 cell culture. In vitro enzymatic activities for recombinant enzymes were decreased in order CBR1 > AKR1C3 > AKR1B1 > AKR1A1 > AKR7A2 > AKR1B10 > AKR1C1 > AKR1C2 > AKR1C4 > CBR3. The...
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 the effect of cyclin-dependent kinase inhibitors on the expression of selected AKR and CBR enzymes in human cell lines.
Kouklíková, Etela ; Novotná, Eva (advisor) ; Wsól, Vladimír (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Etela Kouklíková Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Study of the effect of cyclin-dependent kinase inhibitors on the expression of selected AKR and CBR enzymes in human cell lines Cyclin-dependent kinase inhibitors (CDKi) are considered as a suitable treatment especially in patients with wrong prognosis or advanced stage of cancer. It has only recently been discovered that CDKi are able to influence the activity of some enzymes from aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies. AKR and SDR enzymes belong to a group of carbonyl reducing enzymes that are involved in the metabolism of endobiotics and xenobiotics. An important group of drugs that are metabolized by these enzymes to less efficient compounds are anthracyclines. The aim of this diploma thesis was to find out whether purvalanol A, roscovitin, dinaciclib, AZD5438 and R547 can affect the expression of the most important anthracycline reductases (AKR1A1, AKR1B10, AKR1C3, AKR7A2 and CBR1) in human HepG2 and HL-60 cell lines. Expression of anthracycline reductases in cells exposed to CDKi was evaluated at mRNA level by RT-qPCR and at protein level by Western blotting. The...
Study of resistance in cancer therapy - protein kinase inhibitors influence on activity of selected human reductases I.
Louvarová, Dagmar ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Dagmar Louvarová 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 I. The anthracycline antibiotics are a significant group of drugs for treatment of various types of cancer. Difficulties related to their usage are cardiotoxicity and multiple drug resistance. Many factors are involved in the development of resistance; one of them is inactivation of anthracyclines by the activity of enzymes, human reductases, which are involved in biotransformation of anthracyclines by reducing their carbonyl group. Daunorubicin was selected from the group of anthracycline antibiotics, in which the potential involvement of selected carbonyl reducing enzymes in its metabolism (AKR1A1, AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C3, AKR1C4, CBR1 and CBR3) was subject of verification. The specific activity of selected reductases was determined by UHPLC analysis of the major metabolite, daunorubicinol. The most active reductases were AKR1B10, AKR1C3, AKR1A1 and CBR1. There is a great potential use of cyclin-dependent kinase inhibitors (CDKi) in cancer therapy. Expected effect is primarily...
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 of the effect of cyclin-dependent kinase inhibitors on the expression of selected AKR and CBR enzymes in human cell lines.
Kouklíková, Etela ; Novotná, Eva (advisor) ; Wsól, Vladimír (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Etela Kouklíková Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Study of the effect of cyclin-dependent kinase inhibitors on the expression of selected AKR and CBR enzymes in human cell lines Cyclin-dependent kinase inhibitors (CDKi) are considered as a suitable treatment especially in patients with wrong prognosis or advanced stage of cancer. It has only recently been discovered that CDKi are able to influence the activity of some enzymes from aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies. AKR and SDR enzymes belong to a group of carbonyl reducing enzymes that are involved in the metabolism of endobiotics and xenobiotics. An important group of drugs that are metabolized by these enzymes to less efficient compounds are anthracyclines. The aim of this diploma thesis was to find out whether purvalanol A, roscovitin, dinaciclib, AZD5438 and R547 can affect the expression of the most important anthracycline reductases (AKR1A1, AKR1B10, AKR1C3, AKR7A2 and CBR1) in human HepG2 and HL-60 cell lines. Expression of anthracycline reductases in cells exposed to CDKi was evaluated at mRNA level by RT-qPCR and at protein level by Western blotting. The...
Determination of the expression of enzymes DHRS7B and DHR7C in human tissues
Kozáková, Klára ; Wsól, Vladimír (advisor) ; Štambergová, Hana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Klára Kozáková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: Determination of the expression of enzymes DHRS7B and DHRS7C in human tissues Dehydrogenase/reductase (SDR family) member 7B (DHRS7B) and 7C (DHRS7C) are human enzymes that belong to the short chain dehydrogenase/reductase (SDR) superfamily. This very old and extensive superfamily includes members, which play an important role in different physiological and pathological processes. In spite of that the SDR enzymes are currently more studied, still about half of these enzymes are only poorly characterized, such as DHRS7B and DHRS7C. The aim of this study was the determination of the expression profiles of human enzymes DHRS7B a DHRS7C at mRNA and protein level and thus brings new knowledge of these enzymes. Expression of enzymes was tested in human tissues. RNA was isolated from the samples and used for transcription to cDNA. Obtained cDNA was utilized as a template for qPCR with fluorescence SYBR GREEN I detection. Determination of enzymes at protein level was done in homogenates of human tissues by using a Western blotting with chemiluminescence detection. The level of expression mRNA DHRS7B was strongest in testes...

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