Anna Bejrowska has graduated from Gdansk University of Technology (Poland) in the year 2013. She is a co-author of a paper about environmental tests based on nuclear receptors’ activity changes. Her curiosity and desire for intellectual development is what led her to pursue her PhD in the field of Drug Development. Currently, she is a PhD candidate in the Department of Pharmaceutical Technology and Biochemistry at Gdansk University of Technology. She is consistently developing her experience of working with active compounds, enzyme fractions and cell cultures. Her interest is focused on modulations and differentiation of drugs’ metabolism, including the role of nuclear receptors in those processes.
Modern cancer treatment provides promising outcomes, thanks to the combined therapies. However, aiming to decrease resistance against individual drugs, treatment can intensify their adverse and toxic effects. Therefore, it is important to examine the influence that potential therapeutics have on cellular metabolism. Our group previously revealed that antitumor acridinone derivatives, C-1305 and C-1311, are metabolized to a great extent by UGT1A10. Thus, the aim of the present study is to test the ability of these compounds to modulate the activity of UGT1A10 isoenzyme both in non-cellular and cellular systems. The experiments were performed using human recombinant isoenzyme UGT1A10 and colon cancer line HCT-116 over expressing UGT1A10. Enzyme activity in both models were measured using UGT-specific reaction, 7-hydroxy-4-(trifluoromethyl)-coumarin glucuronidation in the presence of selected acridinone derivatives, as well as without the drug (control experiments) by RP-HPLC analysis. The results showed that, C-1305 and C-1311 act differently towards UGT1A10 activity in dependence on the applied model. Enzymatic activity of UGT1A10 was reduced by both acridinone derivatives in non-cellular system. By contrast, higher level of UGT1A10 activity was observed in HCT-116 cells treated with both studied compounds. It is supposed that C-1305 and C-1311 potentially applied in multidrug therapy might modulate the effectiveness of UGT1A10 on the protein and the transcriptional level. This finding provides new insights into potential pharmacokinetic drug-drug interactions between C-1305 and C-1311 and the substrates of UGT1A10.
Anna Mróz has studied Biotechnology from Gdańsk University of Technology (Poland) and received her Master’s degree in the year 2013. She is now a PhD student at the Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology. Her scientific interests are related to the investigation of metabolism of new active compounds against cancer. She is a co-author of two papers in the field of UDP-glucuronosyltransferases-mediated metabolism.
UDP-glucuronosyltransferases (UGTs) are phase II conjugating enzymes catalyzing glucuronidation reaction of many exogenous and endogenous substances. Glucuronides are more polar than the native compounds which facilitates their excretion. UGT isoenzymes are in the spotlight in respect to antitumor therapy as glucuronidation is the major route of elimination for many anticancer drugs. Moreover, some drug-drug interactions can be explained on the basis of UGTs inhibition. The objective of the present study was to explore the inhibitory effect of C-1748, an acridine antitumor agent, toward isoenzyme UGT1A9 in order to predict the potential for drug-drug interactions. C-1748 showed strong cytotoxic activity against colon cancer cells and high anti-tumor activity against prostate carcinoma xenografts which allowed its selection for preclinical studies. Previous results indicated that C-1748 undergoes glucuronidation with human liver and intestinal microsomes. Our studies showed that C-1748 is not a substrate for UGT1A9, however it exerted dose-dependent inhibition toward this isoenzyme. The glucuronidation reactions of standard substrate 7-hydroxy-4-(trifluoromethyl)coumarin were conducted in the absence or presence of C-1748 and monitored by HPLC/UV-Vis method. The concentration of 0.25 mM of C-1748 inhibited more than 70% activity of UGT1A9. The inhibition kinetic type was determined to be noncompetitive on the basis of Lineweaver-Burk and Dixon plots and the inhibition kinetic parameter (Ki) was calculated to be 0.17 mM. Taking together, the presented UGT1A9 significant inhibition indicates the high possibility for drug-drug interactions in combined therapies using C-1748 anticancer agent. Therefore, clinical monitoring should be applied when co-administrating C-1748 with drugs mainly undergoing UGT1A9-mediated metabolism.