CYP3A4‐dependent cellular response does not relate to CYP3A4‐catalysed metabolites of C‐1748 and C‐1305 acridine antitumor agents in HepG2 cells

Abstract

High CYP3A4 expression sensitizes tumor cells to certain antitumor agents while for others it can lower their therapeutic efficacy. We have elucidated the influence of CYP3A4 overexpression on the cellular response induced by antitumor acridine derivatives, C-1305 and C-1748, in two hepatocellular carcinoma (HepG2) cell lines, Hep3A4 stably transfected with CYP3A4 isoenzyme, and HepC34 expressing empty vector. The compounds were selected considering their different chemical structures and different metabolic pathways seen earlier in human and rat liver microsomes C-1748 was transformed to several metabolites at a higher rate in Hep3A4 than in HepC34 cells. In contrast, C-1305 metabolism in Hep3A4 cells was unchanged compared to HepC34 cells, with each cell line producing a single metabolite of comparable concentration. C-1748 resulted in a progressive appearance of sub-G1 population to its high level in both cell lines. In turn, the sub-G1 fraction was dominated in CYP3A4-overexpressing cells following C-1305 exposure. Both compounds induced necrosis and to a lesser extent apoptosis, which were more pronounced in Hep3A4 than in wild-type cells. In conclusion, CYP3A4-overexpressing cells produce higher levels of C-1748 metabolites, but they do not affect the cellular responses to the drug. Conversely, cellular response was modulated following C-1305 treatment in CYP3A4-overexpressing cells, although metabolism of this drug was unaltered.

Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

“…Based on the liquid chromatography mass spectrometry (LC-MS) data ( Figure 3), two metabolites were predicted to be 1-amino-9-hydroxyethylaminoacridine (M1) and 1nitroacridinone (M2), mammalian metabolites were also previously reported [15,20]. In contrast to the metabolism of the studied compound in human hepatocellular carcinoma cell lines under normoxia, the metabolites profile observed in C. albicans seems to be similar to that obtained for mammalian cells under hypoxia or reducing conditions [15,20]. The main fungal metabolic product M1 (m/z 268.1), 1-amino-9hydroxyethylaminoacridine was detected as the main metabolic product of human cancer cell lines only under a low level of oxygen.…”

“…The elution of sample components were monitored at 380 nm, as it has been shown previously for C-1748 and its metabolites in HepG2 cells [15,20] and at 420 nm.…”

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

“…Moreover, the metabolic profiles of C-1305 and C-1311 were not changed in MCF-7 and HCT116 cells after their overexpression with P4503A4 isoenzyme [47]. Thus, P4503A4 does not take part in the metabolism of studied acridinone derivatives, as we previously showed with recombinant isoenzymes in a non-cellular system [26,27] and in HepG2 cells [29,31]. EV.…”

“…Each compound was also found to be metabolized with human recombinant flavin-containing monooxygenases 1 and 3 (FMO1, FMO3) [27,28]. Although the metabolism of both studied drugs did not depend on P4503A4 expression, the cellular response, including apoptosis, was stronger in P4503A4-overexpressing HepG2 and CHO cells following C-1305 [29,30] and C-1311 [31,32] treatment. It was also demonstrated that the studied compounds underwent UGT-mediated metabolism to 8-O-glucuronides with human liver and intestinal microsomes and particularly with recombinant extrahepatic UGT1A10 isoenzyme [33].…”

Combined anticancer therapy with imidazoacridinone analogue C‐1305 and paclitaxel in human lung and colon cancer xenografts—Modulation of tumour angiogenesis

“…In contrast, another study showed that C‐1305 strongly induced the activity and expression of CYP3A4 and CYP2C9, as well as expression of UDP‐glucuronosyltransferase (UGT) 1A1 and MDR1 in pregnane X receptor‐dependent HepG2 cells 24,25 . Overexpression of CYP2A4 enhanced the apoptosis induced by C‐1305 or C‐1311 in CHO cells 26,27 . Some authors suggest that extrahepatic UGT1A10 also plays an important role in the metabolism and bioactivation of C‐1305, and this biotransformation leads to enhanced proapoptotic activity of these glucuronide products 28,29 .…”