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Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts
Gala, Viktor ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktor Gala Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts The nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) is now the mainstay of combination antiretroviral therapy (cART) for HIV in pregnant women. The introduction of cART, along with several other measures, has reduced mother-to-fetus transmission of HIV to less than 1% in recent years. The placenta is a key organ for the health of both the fetus and the mother. Imbalances in placental development can result in adaptive changes and fetal programming errors. cART recommended in pregnancy is known for its good safety profile, but some epidemiological studies suggest a higher risk of reduced fetal weight, preterm birth, etc. The placenta is a rapidly growing organ dependent on the supply of building materials that resembles tumor growth in certain aspects. Nucleosides are promoters of tumor proliferation and are involved in the development of immunotolerance. The placenta is complexly equipped for nucleoside synthesis, uptake,...
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Evaluation of gene expression of selected ABC and SLC transporters in the HTR-8/SVneo cell line during stimulation with pro-inflammatory cytokines
Pokorná, Petra ; Čečková, Martina (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Petra Pokorná Supervisor: Assoc. Prof. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Dudičová Title of diploma thesis: Evaluation of gene expression of selected ABC and OATP transporters in the HTR-8/SVneo cell line during stimulation with pro-inflammatory cytokines Placenta is the first and the largest fetal organ that gradually develops during pregnancy and plays an essential role in the development of the fetus. It fulfills the entire spectrum of functions, ensures the transport of nutrients to the fetus and the removal of waste substances back into the maternal circulation, protects the fetus from toxins, and at the same time fulfills a certain mechanical and especially immunological barrier between mother and fetus. One of the main functions of the placenta is the transport function which is made possible by membrane transporters present mainly in the syncytiotrophoblast layer of the placenta. Transporters in the human placenta can be divided into two families, SLC and ABC which are further divided into several subfamilies. The expression of transporters changes physiologically during pregnancy, but pathological conditions such as inflammation can also influence the expression....
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Study on interactions of PARP inhibitors with ABC drug efflux transporters
Dziaková, Lucia ; Hofman, Jakub (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucia Dziaková Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study on interactions of PARP inhibitors with ABC drug efflux transporters. ATP-binding cassette (ABC) transporters are integral membrane proteins that use the energy obtained from ATP to carry transport of numerous endogenous substrances out of the cells, but attention is drawn primarily to the fact that they transfer also xenobiotics. Their overexpression in tumor tissue contributes to multidrug resistance (MDR), which in most cases leads to therapy failure. Poly(ADP-ribose)polymerase inhibitors (PARPi) represent a promising therapeutic approach in the treatment of cancers that exhibit defects in homologous recombination (HR). This work focuses on four selected PARPi (olaparib, rucaparib, niraparib, veliparib) and their interaction potential towards ABC drug efflux transporters (ABCB, ABCC1, ABCG2). In our work, we worked with MDCKII cells (parent, transduced by the transporters of interest) and utilized the principle of accumulation studies based on the measurement of fluorescence intensity of specific model substrates (hoechst33342, calcein AM, daunorubicin, mitoxantrone). We used established inhibitors of studied...
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Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts
Gala, Viktor ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktor Gala Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts The nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) is now the mainstay of combination antiretroviral therapy (cART) for HIV in pregnant women. The introduction of cART, along with several other measures, has reduced mother-to-fetus transmission of HIV to less than 1% in recent years. The placenta is a key organ for the health of both the fetus and the mother. Imbalances in placental development can result in adaptive changes and fetal programming errors. cART recommended in pregnancy is known for its good safety profile, but some epidemiological studies suggest a higher risk of reduced fetal weight, preterm birth, etc. The placenta is a rapidly growing organ dependent on the supply of building materials that resembles tumor growth in certain aspects. Nucleosides are promoters of tumor proliferation and are involved in the development of immunotolerance. The placenta is complexly equipped for nucleoside synthesis, uptake,...
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Resistance mechanisms in therapy of acute myeloid leukemia
Suchá, Simona ; Čečková, Martina (advisor) ; Žák, Pavel (referee) ; Matoušková, Petra (referee)
IN ENGLISH LANGUAGE Candidate: Mgr. Simona Suchá Supervisor: Assoc. Prof. PharmDr. Martina Čečková, PhD. Title of the doctoral thesis: Resistance mechanisms in therapy of acute myeloid leukemia Acute myeloid leukemia (AML) is a hematologic cancer known for its extensive heterogeneity, poor treatment outcomes and high relapse rate. Therapy outcome is often compromised by highly resistant leukemic clones present at diagnosis, which evade chemotherapy and continue to spread the disease. Identification of their cellular features is, therefore, a key in successful targeting and eliminating of these resistant leukemic cells. AML cells can, however, develop drug resistance even overtime due to prolonged drug exposure. Extremely high adaptability of leukemic cells enables them to survive whenever therapeutic stress stimuli occur. Uncovering molecular mechanisms that cells utilize to activate their survival mode is crucial in selection of treatment leading to maximal efficacy. Based on these grounds, two main aims of this thesis were set. First, to determine clinical relevance of ABC efflux transporters in AML and to evaluate the effect of targeted agents on chemotherapy. The focus was put on agents belonging to either FLT3 inhibitors (midostaurin) or CDK4/6 inhibitors (abemaciclib, palbociclib,...
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CHARACTERIZATION OF GILTERITINIB-RESISTANT LEUKEMIC CELL LINE
Zlesáková, Lucie ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Zlesáková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá, Ph.D. Title of diploma thesis: Characterization of gilteritinib-resistant leukemic cell line Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis for which therapy failure is often responsible. Development of drug resistance is among the most common causes of treatment failure. The exact mechanisms leading to the resistance are not known, especially for drugs recently introduced into the clinical practice such as gilteritinib. Therefore, the gilteritinib-resistant leukemic cell line (referred to as HL-60 g75) has been established in our lab and further characterized. The aim of this study was to evaluate the sensitivity of HL-60 g75 cells to gilteritinib and to clarify the stability of acquired resistance. We revealed that the resistance of HL-60 g75 cells is transient, since only after 4 weeks of gilteritinib-free cell culture, sensitivity of these cells was restored. While gilteritinib induced apoptosis similarly in both gilteritinib-sensitive (HL-60 wt) and -resistant cells, cell cycle analysis revealed lower responsiveness of HL-60 g75 to gilteritinib than HL-60 wt....
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Evaluation of gene expression of selected ABC and SLC transporters in the HTR-8/SVneo cell line during stimulation with pro-inflammatory cytokines
Pokorná, Petra ; Čečková, Martina (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Petra Pokorná Supervisor: Assoc. Prof. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Dudičová Title of diploma thesis: Evaluation of gene expression of selected ABC and OATP transporters in the HTR-8/SVneo cell line during stimulation with pro-inflammatory cytokines Placenta is the first and the largest fetal organ that gradually develops during pregnancy and plays an essential role in the development of the fetus. It fulfills the entire spectrum of functions, ensures the transport of nutrients to the fetus and the removal of waste substances back into the maternal circulation, protects the fetus from toxins, and at the same time fulfills a certain mechanical and especially immunological barrier between mother and fetus. One of the main functions of the placenta is the transport function which is made possible by membrane transporters present mainly in the syncytiotrophoblast layer of the placenta. Transporters in the human placenta can be divided into two families, SLC and ABC which are further divided into several subfamilies. The expression of transporters changes physiologically during pregnancy, but pathological conditions such as inflammation can also influence the expression....
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The influence of LDL-apheresis on aggregation of blood platelets, blood coagulation, and the effect of standard drugs.
Černotová, Veronika ; Mladěnka, Přemysl (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Černotová Supervisor: prof. Přemysl Mladěnka, PharmD., Ph.D. Consultant: Lukáš Konečný, MSc. Title of diploma thesis: The influence of LDL-apheresis on aggregation of blood platelets, blood coagulation and the effect of standard drugs LDL-apheresis is a method that removes LDL-cholesterol (LDL-C) from the blood. It is used to treat familial hypercholesterolemia (FH), a genetic disorder causing high LDL-C levels and an early development of cardiovascular diseases. Blood platelets and coagulation system play an important role in these diseases and their activity is also affected by lipids. The aim of this thesis was to analyze possible differences in platelet aggregation and blood coagulation in patients suffering from FH. Two methods of treatment in this group were compared - lipid apheresis and PCSK9Ab (proprotein convertase subtilisin/kexin type 9 monoclonal antibodies). The observed parameters were also compared with age-matched healthy volunteers. Our cohort consisted of 15 patients and 15 healthy donors. Six patients were treated with lipid apheresis and also PCSK9Ab, six subjects only with PCSK9Ab. Platelet aggregation was measured with an impedance aggregometer using 7 different...
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Resistance mechanisms in therapy of acute myeloid leukemia
Suchá, Simona ; Čečková, Martina (advisor) ; Žák, Pavel (referee) ; Matoušková, Petra (referee)
IN ENGLISH LANGUAGE Candidate: Mgr. Simona Suchá Supervisor: Assoc. Prof. PharmDr. Martina Čečková, PhD. Title of the doctoral thesis: Resistance mechanisms in therapy of acute myeloid leukemia Acute myeloid leukemia (AML) is a hematologic cancer known for its extensive heterogeneity, poor treatment outcomes and high relapse rate. Therapy outcome is often compromised by highly resistant leukemic clones present at diagnosis, which evade chemotherapy and continue to spread the disease. Identification of their cellular features is, therefore, a key in successful targeting and eliminating of these resistant leukemic cells. AML cells can, however, develop drug resistance even overtime due to prolonged drug exposure. Extremely high adaptability of leukemic cells enables them to survive whenever therapeutic stress stimuli occur. Uncovering molecular mechanisms that cells utilize to activate their survival mode is crucial in selection of treatment leading to maximal efficacy. Based on these grounds, two main aims of this thesis were set. First, to determine clinical relevance of ABC efflux transporters in AML and to evaluate the effect of targeted agents on chemotherapy. The focus was put on agents belonging to either FLT3 inhibitors (midostaurin) or CDK4/6 inhibitors (abemaciclib, palbociclib,...
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Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells
Králová, Adéla ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Králová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá Title of Diploma thesis: Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells Fms-like tyrosine kinase 3 (FLT3) inhibitors represent a new generation of drugs in the treatment of acute myeloid leukemia (AML). Standard therapeutic regimen of AML is initiated with induction therapy consisting of cytarabine and anthracyclines. The disadvantage of this combination is emerging resistance often caused by the ABCB1-mediated efflux. Therefore, simultaneous inhibition of FLT3 and ABCB1, which is inhibited by FLT3 inhibitors used in clinical practice, appears to be a beneficial approach to therapy. However, their effectiveness is declining hence the effort to develop new FLT3-inhibiting molecules. The aim of our work was to evaluate whether our two promising new FLT3-inhibiting compounds would inhibit ABCB1 as well. Promyelocyte cells overexpressing ABCB1 (HL60-ABCB1) and parent HL60-par were used in this study alongside AML-derived cell lines (MOLM-13, THP-1, Kasumi-1). Employing accumulation studies on HL60-ABCB1, strong inhibitory effect towards ABCB1 was demonstrated...
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