Przełamywanie oporności wielolekowej nowotworów na poziomie genomu: opracowanie metody zapobiegającej nadekspresji transporterów ABC w komórkach nowotworowych opartej na inhibitorach enzymów remodelujących chromatynę

Abstract

Despite years of research and scientists' efforts to develop novel therapies, cancer is still the second most common cause of death in Poland, and chemotherapy is the most widely used treatment. Nearly half of patients with triple-negative breast cancer experience a relapse after treatment with this type of therapy. This phenomenon is due to the acquisition of multidrug resistance (MDR) as a result of stress factors such as hypoxia, radio- and chemotherapy. Cells with MDR are characterized by decreased sensitivity to cytostatics through, among other things, overexpression of ABC transporters and polynucleation. In a previous work by our team, it was shown that induction of cisplatin resistance in the A549 and MDA-MB-231 cell lines led to the appearance of p300 acetyltransferase on the promoter of the ABCC10 gene. Therefore, in the first part of the study, the effect of the CBP/p300 bromodomain inhibitor I-CBP112 on the downregulation of ABC transporter expression in baseline and clinically relevant, induced resistance lines MDA-MB-231 and A549 was described. In addition, the safety profile of the test compound against normal lines was verified, as well as the ability of I-CBP112 to induce and enhance poly(aneu)ploidy, which is among the mechanisms of cancer cell resistance. Complementary to the present experiments, we prepared two review papers on the phenomenon of polynucleation in cancer, as well as a comparison of pharmacokinetic properties, ADMET parameters and collateral targets of commercially available CBP/p300 inhibitors differing in their mechanism of action. Considering that PARP1 protein is a correlator of CBP/p300 action, in the second part of the thesis I focused my attention on the effect of PARP1/HPF1 complex on the regulation of ABC transporter expression, as well as identification of the transcription factor responsible for PARP1 dependent transcription of ABCC3, ABCC4 and ABCC5 genes.