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Inhibitory effect of tepotinib, entrectinib, and sapanisertib on an activity of selected reductases from AKR superfamily.
Krtilová, Kamila ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Kamila Krtilová Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: Inhibitory effect of tepotinib, entrectinib, and sapanisertib on an activity of selected reductases from AKR superfamily. The lung carcinoma has an increasing trend in the Czech Republic. These findings correspond to the fact that lung carcinoma is the most common type of cancer worldwide. Carbonyl reducing enzymes occur in different types of tissues, and they are responsible for the development of inflammation, cancer, and cancer resistance. These NADPH-dependent oxidoreductase cause the reduction of carbonyl groups to alcohol compound and decrease the toxicity of drug for tumor cells. Last but not least, these enzymes are responsible for tumor cell proliferation, differentiation, and increased tumoral aggressivity. This work aimed to study the inhibition effect of chosen cyclin-dependent kinase inhibitors (CDKi) on the activity of Aldo-keto reductases. Besides inhibition of CDK, the ability to inhibit efflux transporters and carbonyl reducing enzymes was proved at CDK inhibitors. The inhibition effect of tepotinib, entrectinib and sapanisertib was determined by UHPLC analysis. The most significant inhibition...
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Optimization of PEI based LbL capsules with pDNA
Ondrašáková, Petra ; Mladěnka, Přemysl (advisor) ; Hofman, Jakub (referee)
Ab rac Charle Uni er i Fac l of Pharmac in Hradec Kr lo Depar men of Pharmacolog and To icolog S den : Pe ra Ondra ko , MSc. S per i or: A oc. Prof. P em l Mlad nka, Pharm.D., Ph.D. Co- per i or: Dr. Haider Sami, Uni er i of Vienna, Di i ion of Clinical Pharmac and Diagno ic Ti le of rigoro he i : Op imi a ion of PEI ba e LbL cap le i h pDNA In hi he i , e foc ed on he de elopmen of pol e h lenimine (PEI) ba ed non- iral cap le , hich ill en er n cle of he cancer cell and lead o he e pre ion of he lacking pro ein, hich ca e di ea e. A fir , PEI ba ed la er-b -la er (LbL) pol mer cap le ere formed. PEI ha man ad an age - i ha pro onable amine , good abili and ran fec ion efficienc . When forming he cap le, I follo ed p on m diploma he i and con in ed o op imi e he mo i able combina ion of pol mer , ha ere la ered on he CaCO3core. The aim a o ob ain a biodegradable cap le and hen o incorpora e pla mid DNA (pDNA) herein. Fl ore cen l labelled PEI a ed a he la la er o i ali e par icle in fl ore cen micro cope. Then a canning elec ron micro cope (SEM) a ed o ob er e cap le in more de ail . UV-VIS and Dapi aining ere ed o ee he her here i pDNA bo nd in cap le . Ne ep ere i i cell e perimen on mo e mammar cancer cell - c o o ici and cell lar in ake. Vi ali a ion a pro ided i h fl ore cen micro cop . 2 pe of...
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The effect of alisertib and brigatinib on the activity of selected human carbonyl reducing enzymes.
Lakomá, Petra ; Novotná, Eva (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Petra Lakomá Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: The effect of alisertib and brigatinib on the activity of selected human carbonyl reducing enzymes Key words: brigatinib, alisertib, daunorubicin, inhibition, carbonyl-reducing enzymes Protein kinases are enzymes, whose main function is based on a transfer of phosphate group from ATP to protein substrate. This common posttranslational modification is involved in the regulation of intracellular processes and cell signaling. Altered expression of protein kinases is often coupled with a development of cancer. Inhibition of protein kinases may prevent cancer cell proliferation and induce their cell death. The main aim of the diploma thesis was to measure inhibition potential of protein kinase inhibitors, alisertib and brigatinib, against carbonyl-reducing enzymes. Overexpression of carbonyl-reducing enzymes in cancer cells may cause resistance to drugs followed by failure of chemotherapeutic therapy. In case of antracyclin chemotherapeutic daunorubicin, carbonyl-reducing enzymes reduce the carbonyl in C-13 giving rise a primary metabolite daunorubicinol, which has lower cytotoxic effect but higher cardiotoxicity. The effort to...
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Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors
Vagiannis, Dimitrios ; Hofman, Jakub (advisor) ; Souček, Pavel (referee) ; Zendulka, Ondřej (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Dimitrios Vagiannis Supervisor RNDr. Jakub Hofman, Ph.D. Title of Doctoral Thesis Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors Cancer chemotherapy is an important tool for the cure of cancer. Although the development of new anticancer drugs has been rapidly progressing, the phenomenon of multidrug resistance (MDR) continues to be a key issue leading to therapy failure in oncological patients. MDR is based on pharmacodynamic as well as pharmacokinetic mechanisms. Pharmacokinetic MDR includes drug efflux transporters and biotransformation enzymes that decrease the amount of (active form of) a drug in tumors. While the MDR role of transporters has been well understood, the participation of drug metabolizing enzymes is still unclear. This thesis investigates the role of cytochromes P450 (CYPs) in cytostatic resistance. Furthermore, it focuses on the modulation of pharmacokinetic MDR using pharmacokinetic drug-drug interactions of new targeted antitumor drugs. Finally, it aims to confirm the in vitro findings in ex vivo patient-derived tumor explants. In our latest publication, we demonstrate the significant role of...
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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...
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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...
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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:...
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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,...
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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,...
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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...
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