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.

c-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells

“…Studies have shown that C-1311 is a DNA intercalator and topoisomerase II inhibitor [ 54 ]. It caused the accumulation of cells in the G2/M phase and subsequent induction of apoptosis, necrosis, autophagy, mitotic catastrophe or accelerated senescence, wherein apoptosis was not the main cause of cell death in solid cancer cell lines, especially HCT116 [ 55 ] and H460 cells [ 56 ]. Therefore, it should be emphasized that the presented studies showed that UAs exhibit an entirely different cellular mechanism of action to C-1311.…”

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

“…28,29 Interestingly, although both C-1305 and C-1311 undergo metabolic transformation to the glucuronidated forms upon overexpression of UGT1A10, UGT1A10 overexpression significantly increased the cytotoxicity of C-1305 but not C-1311. 28,29 These findings contribute to the understanding of the mechanisms of action of both compounds and encourage further studies on the C-1305 mode of action.…”

“…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 Interestingly, although both C-1305 and C-1311 undergo metabolic transformation to the glucuronidated forms upon overexpression of UGT1A10, UGT1A10 overexpression significantly increased the cytotoxicity of C-1305 but not C-1311. 28,29 These findings contribute to the understanding of the mechanisms of action of both compounds and encourage further studies on the C-1305 mode of action.…”

“…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 . Interestingly, although both C‐1305 and C‐1311 undergo metabolic transformation to the glucuronidated forms upon overexpression of UGT1A10, UGT1A10 overexpression significantly increased the cytotoxicity of C‐1305 but not C‐1311 28,29 .…”

Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells

“…Another aspect of the results described above is illustrated by Figure 9 , Figure 10 and Figure 11 . HPLC analysis indicated that HT-29 tumor cells, which are characterized by the highest levels of metabolic enzymes [ 79 ], are also the most susceptible to drug accumulation. This relates to all three studied compounds, but particularly to those possessing the additional methyl group in the acridine ring, C-2045 and C-2053.…”