Study of resistance in cancer therapy - protein kinase inhibitors influence on activity of selected human reductases I

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...