Several classes of highly potent antitumor derivatives were developed at our Department. The imidazoacridinone derivative C-1311 has recently entered phase II clinical trials. The most active derivative of 4-methyl-1-nitroacridines C-1748 has been prepared for the phase I clinical trials. Among triazoloacridinones, the compound C-1305 is currently undergoing extended pre-clinical studies.

Our previous studies showed that metabolic activation of acridine antitumor agents was crucial for biological action of these compounds. It was also reported that the expression level of enzymes responsible for drug metabolism altered cell cycle progression and cellular response induced by these drugs.

The aim of current studies was to examine the influence of mentioned above acridine derivative on the cell cycle progression as well as the ability of these drugs to induce cell death of human hepatoma cells. HepG2 cells, stably expressing the P450 enzyme CYP3A4 (Hep3A4) and HepG2 cells were selected for these studies. All experiments were performed at biological relevant doses of the drugs (EC₅₀ and EC₈₀ concentrations). Hep3A4 cells were more sensitive than HepG2 cells to C-1748 treatment (EC₈₀ = 0,05 µM for Hep3A4 and 0,7 µM for HepG2) and to C-1305 treatment (EC₅₀ = 0,8 µM for Hep3A4 and 1,6 µM for HepG2). On the contrary, imidazoacridinone derivative C-1311 exhibited almost the same cytotoxic activity towards both human hepatoma cells (EC₅₀ = 1,73 µM for Hep3A4 and 1,18 µM for HepG2).

The morphological changes of hepatoma cells treated with studied acridine derivatives for different times (3 – 144 h) were performed using fluorescence microscopy (DAPI staining). HepG2 cells showed alterations of the nuclear morphology (condensed chromatin, apoptotic body-like structures), but only in limited part of cell populations. The morphological observation of Hep3A4 cells showed the appearance of few cells with characteristic apoptotic morphology, concomitantly with the appearance of the enlarged cells with multiple micronuclei, typical for mitotic catastrophe. The population of the multinucleated cells increased after prolonged incubation with drugs.

Effect of acridine derivatives on the human hepatoma progression through cell cycle was analyzed by flow cytometry. HepG2 cells underwent a short-term G2M accumulation after 24 h of C-1305 treatment (~30%). The G2M arrest started from 12 h and increased during prolonged incubation with C-1311 (65% after 144 h). C-1748 did not induce any significant changes in the cell cycle distribution of HepG2 cells. However, gradual increase in the number of apoptotic sub-G1 fraction of cells was observed after all acridine derivatives treatment.

These results indicate that acridine derivatives, induce different cellular response (apoptosis, mitotic catastrophe) in human hepatoma cells with various expression level of cytochrome P450 isoenzymes.

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1. Glucuronidation of antitumor agents - detoxification, mechanism of drug resistance or the prodrug design? Studies on acridine antitumor agents in the light of clinical therapeutics
2. Antitumor triazoloacridinone C-1305 as a potent FLT3 tyrosine kinase inhibitor in human leukemia MV4;11 cells.
3. Metabolism of antitumor 9-amino-1-nitroacridine derivative C-1748 (Capridine-beta) in human hepatoma HepG2 cells
4. The role of hepatic cytochrome P-450 enzymes in metabolism of imidazoacridinone antitumor agent, C1311 (Symadex^R): studies with the hepatic NADPH:cytochrome P450 reductase null mice
5. Imidazoacridinone antitumor agent, C-1311, as a selective mechanism-based inactivator of human recombinant cytochrome P450 1A2.
6. Effects on cell cycle distribution and induction of apoptosis of human breast carcinoma MCF7 cells by imidazoacridinone C-1311
7. The role of Cytochrome P450 Reductase in metabolism of potent nitroacridine antitumor agent, C‑1748.
8. The cellular response of human colon carcinoma HCT116 cells to 4-methyl-1-nitroacridine derivative C-1748 treatment depending on p53 status.
9. METABOLIC TRANSFORMATIONS OF ANTITUMOR AGENTS WITH CYTOCHROME P-450 ISOENZYMES.