Antitumor 4-methyl-1-nitroacridine derivative C-1748 is currently being prepared for the phase I of clinical trials. This compound was shown to exert potent anticancer activity against several prostate cancer of human origin and colon carcinoma xenografts in nude mice. Here, we investigated some cellular response of human colon carcinoma cells HCT116 to C-1748 treatment in relation to p53 function.

HCT116 p53^+/+and HCT116 p53^-/- cells were incubated with increasing concentrations of C-1748 for 72 h and inhibition of cell proliferation was estimated by cell counting using Coulter Counter. The 4-methyl-1-nitroacridine derivative inhibited proliferation of both HCT116 cell lines in a dose-dependent manner. However, HCT116 p53- null cells were two times more sensitive to C-1748 than cells expressing p53 (EC_{90 HCT116 p53}^+/+= 0,03 µM ± 0,02; EC_{90 HCT116 p53}^-/-= 0,016 µM ± 0,007).

Next, HCT116 p53^+/+and HCT116 p53^-/- cells were treated with C-1748 at EC₉₀ concentration for different time periods (from 24 h to 120 h). In both cell lines, 24 h of incubation with the drug resulted in the appearance of hypodiploid cells (sub-G1 fraction), suggesting initiation of apoptosis. The percentage of sub-G1 cells was greater in the case of HCT116 p53^+/+ compared to p53-null cells. Higher concentration of C-1748 (5 x EC₉₀) did not cause any significant increase in the amount of sub-G1 cells in both cell lines even after prolonged treatment (120 h).

Apoptotic commitment was further confirmed by additional criteria: nuclear morphology (DAPI staining) and plasma membrane alterations (Annexin V/PI assay). After 24 h of incubation with C-1748 (EC₉₀ concentration) cells with typical apoptotic morphology were observed in both cell lines, however apoptotic bodies were more frequent in the case of HCT116 p53^+/+ cells. Moreover, enlarged cells with multiple micronuclei, typical for mitotic catastrophe, appeared after 24 h in the case of HCT116 p53^-/- cells, whereas only occasional multinuclei were observed in HCT116 p53^+/+ cells at the same time points of treatment. At higher concentration of C-1748 (5 x EC₉₀) there was no increase in the amount of apoptotic cells in both cell lines. However, after treatment of HCT116 p53^-/- cells with 5 x EC₉₀ concentration of the drug, micronucleated cells were not observed.

Membrane alterations induced in C-1748-treated cells (Annexin V/PI assay) were observed in 25% of HCT116 p53^+/+ cells and in 10% of HCT116 p53^-/- cells after 24 h of incubation with the drug.

In conclusion, following C-1748 treatment, cells expressing p53 were more prone to undergo apoptosis than p53-null cells.

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