Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response
Activity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studi...
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MDPI AG
2020-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/11/3954 |
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| author | Monika Pawłowska Anna Kwaśniewska Zofia Mazerska Ewa Augustin |
| author_facet | Monika Pawłowska Anna Kwaśniewska Zofia Mazerska Ewa Augustin |
| author_sort | Monika Pawłowska |
| collection | DOAJ |
| description | Activity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studies in non-cellular systems showed that they are mechanism-based inhibitors of cytochrome P4503A4 and undergo glucuronidation via UDP-glucuronosyltranspherase 1A10 isoenzyme (UGT1A10). Therefore, we investigated the potency of these compounds to modulate P4503A4 and UGT1A10 activity in breast MCF-7 and colon HCT116 cancer cells and their influence on cytotoxicity and cellular response in cells with different expression levels of studied isoenzymes. We show that C-1305 and C-1311 are inducers of not only P4503A4 but also UGT1A10 activity. MCF-7 and HCT116 cells with high P4503A4 activity are more sensitive to acridinone derivatives and undergo apoptosis/necrosis to a greater extent. UGT1A10 was demonstrated to be responsible for C-1305 and C-1311 glucuronidation in cancer cells and glucuronide products were excreted outside the cell very fast. Finally, we show that glucuronidation of C-1305 antitumor agent enhances its pro-apoptotic properties in HCT116 cells, while the cytotoxicity and cellular response induced by C-1311 did not change after drug glucuronidation in both cell lines. |
| first_indexed | 2024-03-10T19:28:28Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:28:28Z |
| publishDate | 2020-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3029e9d7cee047eeab92d9ff00d226a02023-11-20T02:22:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-012111395410.3390/ijms21113954Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular ResponseMonika Pawłowska0Anna Kwaśniewska1Zofia Mazerska2Ewa Augustin3Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, 80-233 Gdańsk, PolandNencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandDepartment of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, 80-233 Gdańsk, PolandDepartment of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, 80-233 Gdańsk, PolandActivity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studies in non-cellular systems showed that they are mechanism-based inhibitors of cytochrome P4503A4 and undergo glucuronidation via UDP-glucuronosyltranspherase 1A10 isoenzyme (UGT1A10). Therefore, we investigated the potency of these compounds to modulate P4503A4 and UGT1A10 activity in breast MCF-7 and colon HCT116 cancer cells and their influence on cytotoxicity and cellular response in cells with different expression levels of studied isoenzymes. We show that C-1305 and C-1311 are inducers of not only P4503A4 but also UGT1A10 activity. MCF-7 and HCT116 cells with high P4503A4 activity are more sensitive to acridinone derivatives and undergo apoptosis/necrosis to a greater extent. UGT1A10 was demonstrated to be responsible for C-1305 and C-1311 glucuronidation in cancer cells and glucuronide products were excreted outside the cell very fast. Finally, we show that glucuronidation of C-1305 antitumor agent enhances its pro-apoptotic properties in HCT116 cells, while the cytotoxicity and cellular response induced by C-1311 did not change after drug glucuronidation in both cell lines.https://www.mdpi.com/1422-0067/21/11/3954acridinone derivativesanticancer drugsP4503A4 isoenzymeUGTsenzymatic activitydrug metabolism |
| spellingShingle | Monika Pawłowska Anna Kwaśniewska Zofia Mazerska Ewa Augustin Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response International Journal of Molecular Sciences acridinone derivatives anticancer drugs P4503A4 isoenzyme UGTs enzymatic activity drug metabolism |
| title | Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response |
| title_full | Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response |
| title_fullStr | Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response |
| title_full_unstemmed | Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response |
| title_short | Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response |
| title_sort | enhanced activity of p4503a4 and ugt1a10 induced by acridinone derivatives c 1305 and c 1311 in mcf 7 and hct116 cancer cells consequences for the drugs cytotoxicity metabolism and cellular response |
| topic | acridinone derivatives anticancer drugs P4503A4 isoenzyme UGTs enzymatic activity drug metabolism |
| url | https://www.mdpi.com/1422-0067/21/11/3954 |
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