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The assessment of inhibitory effects of selected targeted anticancer drugs on the activity of ABC drug efflux transporters
Jurčáková, Júlia ; Hofman, Jakub (advisor) ; Šorf, Aleš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Júlia Jurčáková Supervisor: RNDr. Jakub Hofman PhD. Title of diploma thesis: The assessment of inhibitory effects of selected targeted anticancer drugs on the activity of ABC drug eflux trasporters. Lung cancer is the leading cause of death within oncological diseases. Non-small cell lung carcinoma (NSCLC) accounts for about 85% of all lung cancer, and its major subtypes include adenocarcinoma and squamous cell carcinoma. In addition to surgery, radiotherapy and chemotherapy, the use of targeted low-molecular substances, which target tumor cells with higher specificity, has recently been used in treatment. The two main causes of death in cancer patients are the formation of metastases and the development of multidrug resistance (MDR). This may also be caused by overexpression of the efflux transporters. ATP-binding cassette (ABC) transporters are groups of transmembrane pumps that use energy in the form of ATP to transfer a wide range of substrates. In particular, P-glycoprotein (ABCB1), breast cancer-resistance protein (ABCG2) and multidrug resistance-associated protein 1 (ABCC1) are associated with MDR. Inhibition of these transporters increases the amount of cytostatic substrate within the...
Interaction of gilteritinib with OCT1 and OCT2 transporters; relation to conventional therapy of acute myeloid leukemia.
Novotná, Kateřina ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Univerzita Karlova Farmaceutická fakulta v Hradci Králové Katedra Farmakologie a toxikologie Student: Kateřina Novotná Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Interaction of gilteritinib with OCT1 and OCT2 transporters; relation to conventional therapy of acute myeloid leukemia. Gilteritinib is one of the recently approved drugs which is primarily used in the treatment of relapsed/refractory acute myeloid leukemia (AML) with mutated FMS-like tyrosine kinase 3 (FLT3) receptor. In this project, gilteritinib was investigated in terms of its ability to interact with solute carrier (SLC) membrane transporters, namely with OCT1 and OCT2. These membrane proteins play a role in uptake of endogenous compounds and also drugs into the cells of main elimination organs (liver, kidney), but also to cancer cells. In particular, we wanted to examine potential interaction with daunorubicin and mitoxantrone, drugs traditionally used in AML therapy. First, we performed accumulation study and evaluated, whether gilteritinib is potential inhibitor of OCT1 and OCT2 studying differential uptake of daunorubicin and mitoxantrone into MDCKII-OCT1 and MDCKII-OCT2 cells based on OCT1 and OCT2 inhibition by gilteritinib. Secondly, the study evaluating the transfer of gilteritinib across the...
The influence of enasidenib, glasdegib, and quizartinib inhibition on the activity of selected reductases from AKR and SDR superfamilies.
Pěčková, Alexandra ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Alexandra Pěčková Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The influence of enasidenib, quizartinib and glasdegib inhibition on the activity of selected reductases from AKR and SDR superfamilies Acute myeloid leukemia is the most common cancerous disease among the adult population. The treatment is dependent on many factors, where the effectiveness of anthracycline antibiotic cytostatic treatment plays a significant role. Therapy is often complicated by resistance to anthracyclines. This resistance can be caused by carbonyl reducing enzymes which also may aid in tumor growth. Carbonyl reducing enzymes are NAD(P)H-dependent oxidoreductases, reducing anthracyclines to respective alcohols, which not only have lower toxicity towards the cancerous cells, but can also damage the cardiac tissue. These enzymes also aid in the differentiation and proliferation of cancerous cells and increase the tumor aggressiveness. The topic of this thesis was to study the inhibitors of carbonyl-reducing enzymes from aldo-keto reductase and short chain dehydrogenase/reductase superfamilies, reducing daunorubicin to less effective metabolite daunorubicinol. The three selected inhibitors were:...
Flow-cytometric analysis of inhibitory effect of novel targeted drugs on the activity of ABC drug efflux transporters
Burianová, Gabriela ; Hofman, Jakub (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Pharmacology & Toxicology Student: Gabriela Burianova Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Flow-cytometric analysis of inhibitory effect of novel targeted drugs on the activity of ABC drug efflux transporters Cancer is the second leading cause of death. Cancer treatment often combines conventional chemotherapy, radiation therapy and surgery. More recent approach to treatment is the use of targeted cancer therapy with a greater specificity towards cancer cells. Development of resistance is a major obstacle in the success of chemotherapy. Multidrug resistance (MDR) can be acquired through various mechanisms e.g. overexpression of efflux transporters. ATP binding cassette (ABC) transporters represents a large family of transmembrane proteins that use ATP to pump molecules across the membrane. The three main ABC proteins related to MDR are: P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Use of ABC transporter inhibitors increases the amount of chemotherapeutical substrates accumulated within the cells. In this study we evaluated interactions of six synthetic small molecule inhibitors (alisertib, ensartinib, entrectinib, talazoparib,...
Flow-cytometric analysis of inhibitory effect of novel targeted drugs on the activity of ABC drug efflux transporters
Burianová, Gabriela ; Hofman, Jakub (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Pharmacology & Toxicology Student: Gabriela Burianova Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Flow-cytometric analysis of inhibitory effect of novel targeted drugs on the activity of ABC drug efflux transporters Cancer is the second leading cause of death. Cancer treatment often combines conventional chemotherapy, radiation therapy and surgery. More recent approach to treatment is the use of targeted cancer therapy with a greater specificity towards cancer cells. Development of resistance is a major obstacle in the success of chemotherapy. Multidrug resistance (MDR) can be acquired through various mechanisms e.g. overexpression of efflux transporters. ATP binding cassette (ABC) transporters represents a large family of transmembrane proteins that use ATP to pump molecules across the membrane. The three main ABC proteins related to MDR are: P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Use of ABC transporter inhibitors increases the amount of chemotherapeutical substrates accumulated within the cells. In this study we evaluated interactions of six synthetic small molecule inhibitors (alisertib, ensartinib, entrectinib, talazoparib,...
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...
Role of drug transporters in placental transfer of entecavir
Lukášová, Veronika ; Červený, Lukáš (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Křečková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Role of drug transporters in placental transfer of entecavir Entecavir (ETV), an analogue of guanosine, is a highly efficient anti-hepatitis B antiviral drug. It is the first-line therapy for both adults and children. Its use in pregnancy is limited due to a number of factors, including lack of data on placental pharmacokinetics. The placental transition of drugs is frequently controlled by drug transporters. ATP-binding (ABC) transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or multidrug resistance-associated protein 2 (MRP2) localized in the apical membrane of syncytiotrophoblast and pumping their substrates in the feto-maternal direction belong to most significant determinants of placental pharmacokinetics. Moreover placental transport of nucleoside-derived drugs can be affected by the activity of nucleoside transporters (NTs); equilibrative nucleoside transporters (ENTs) mediate facilitated diffussion, while the concentrative nucleoside transporters (CNTs) control active influx of their substrates. The aim of the diploma thesis was to describe the role of P-gp, BCRP, MRP2 and NTs (ENTs and...
Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance
Poráč, Jakub ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jakub Poráč Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance P-gp and BCRP are transmembrane proteins that form part of a large family of ABC transporters. These are ATP-driven transporters, which main task is to eliminate exogenous and endogenous substances and their metabolites from cells of both, healthy and tumour tissues. This activity is often associated with the expulsion of administered therapeutics and multiple drug resistance (MDR) in tumour cells. A promising therapy of cancer represents a newer class of drugs target the tyrosine kinase (TK), and cyclin-dependent kinases (CDK), which are cell enzymes responsible for the processes of proliferation, apoptosis and differentiation. Cyclin- dependent kinase inhibitors (CDKI) are used in the treatment of breast cancer, but at the same time they form a new group of drugs with the potential for use in hematological malignancies. In the treatment of AML, a new successful approach is TK inhibitors (TKI), which target the mutated FLT3 receptor, specifically the recently approved drugs midostaurin and...
Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases
Odvárková, Anna ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Anna Odvárková Supervisor: RNDr. Jakub Hofman, Ph.D. Consultants: Carina Lemke Prof. Dr. Michael Gütschow Title of diploma thesis: Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases Cysteine cathepsins are proteases which are naturally present in the human body, taking part in various physiological processes such as cell signaling, proliferation or bone remodeling. However, their dysregulation leads to serious disorders. An aberrant activity of cysteine cathepsins is present in diseases like cancer, osteoporosis, neurodegenerative disorders or autoimmune diseases. Therefore, these enzymes can serve as valuable diagnostic or therapeutic targets. Rhodesain is a parasitic protease produced by Trypanosoma brucei rhodesiense and essential for its survival. This enzyme shares a high homology with human cysteine cathepsin L. Inhibition of rhodesain can be a potential treatment of African trypanosomiasis, also known as sleeping sickness. Inhibitory potency of several compounds against the target enzymes was assayed spectrophotometrically or fluorometrically and the results were evaluated by using linear or non-linear regression. Determination of a Michaelis- Menten constant...
Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases
Odvárková, Anna ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Anna Odvárková Supervisor: RNDr. Jakub Hofman, Ph.D. Consultants: Carina Lemke Prof. Dr. Michael Gütschow Title of diploma thesis: Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases Cysteine cathepsins are proteases which are naturally present in the human body, taking part in various physiological processes such as cell signaling, proliferation or bone remodeling. However, their dysregulation leads to serious disorders. An aberrant activity of cysteine cathepsins is present in diseases like cancer, osteoporosis, neurodegenerative disorders or autoimmune diseases. Therefore, these enzymes can serve as valuable diagnostic or therapeutic targets. Rhodesain is a parasitic protease produced by Trypanosoma brucei rhodesiense and essential for its survival. This enzyme shares a high homology with human cysteine cathepsin L. Inhibition of rhodesain can be a potential treatment of African trypanosomiasis, also known as sleeping sickness. Inhibitory potency of several compounds against the target enzymes was assayed spectrophotometrically or fluorometrically and the results were evaluated by using linear or non-linear regression. Determination of a Michaelis- Menten constant...

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15 Hofman, JAkub
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10 Hofman, Jiří
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