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Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells
Abstract
New unsymmetrical bisacridines (UAs) demonstrated high activity not only against a set of tumor cell lines but also against human tumor xenografts in nude mice. Representative UA compounds, named C-2028, C-2045 and C-2053, were characterized in respect to their physicochemical properties and the following studies aimed to elucidate the role of metabolic transformations in UAs action. We demonstrated with phase I and phase II enzymes in vitro and in tumors cells that: (i) metabolic products generated by cytochrome P450 (P450), flavin monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) isoenzymes in noncellular systems retained the compound’s dimeric structures, (ii) the main transformation pathway is the nitro group reduction with P450 isoenzymes and the metabolism to N-oxide derivative with FMO1, (iii), the selected UGT1 isoenzymes participated in the glucuronidation of one compound, C-2045, the hydroxy derivative. Metabolism in tumor cells, HCT-116 and HT-29, of normal and higher UGT1A10 expression, respectively, also resulted in the glucuronidation of only C-2045 and the specific distribution of all compounds between the cell medium and cell extract was demonstrated. Moreover, P4503A4 activity was inhibited by C-2045 and C-2053, whereas C-2028 affected UGT1A and UGT2B action. The above conclusions indicate the optimal strategy for the balance among antitumor therapeutic efficacy and drug resistance in the future antitumor therapy.
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Authors (8)
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Anna M. Nowicka
- Uniwersytet Warszawski, Wydział Chemii
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Agata Kowalczyk
- Uniwersytet Warszawski, Wydział Chemii
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
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Pharmaceuticals
no. 14,
ISSN: 1424-8247 - Language:
- English
- Publication year:
- 2021
- Bibliographic description:
- Mieszkowska A., Nowicka A. M., Kowalczyk A., Potęga A., Pawłowska M., Kosno M., Augustin E., Mazerska Z.: Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells// Pharmaceuticals -Vol. 14,iss. 4 (2021), s.317-
- DOI:
- Digital Object Identifier (open in new tab) 10.3390/ph14040317
- Sources of funding:
- Verified by:
- Gdańsk University of Technology
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