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.

Abstract

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.

• Authors: Monika Pawłowska, Anna Kwaśniewska, Zofia Mazerska, Ewa Augustin
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 11 (May 31 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32486425 (Publication Type: Journal Article)

Chemical References

• Acridines
• Aminoacridines
• Antineoplastic Agents
• C 1305
• Glucuronides
• Isoenzymes
• Triazoles
• Cytochrome P-450 CYP3A
• bilirubin uridine-diphosphoglucuronosyl transferase 1A10
• Glucuronosyltransferase
• C 1311

Topics

• Acridines (pharmacology)
• Aminoacridines (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Biotransformation
• Cell Line, Tumor
• Cytochrome P-450 CYP3A (metabolism)
• Drug Design
• Drug Screening Assays, Antitumor
• Glucuronides (metabolism)
• Glucuronosyltransferase (metabolism)
• HCT116 Cells
• Humans
• Isoenzymes
• MCF-7 Cells
• Membrane Potential, Mitochondrial
• Necrosis
• Substrate Specificity
• Triazoles (pharmacology)