The cytotoxic activity of the imidazoacridinone
C1311 was assessed on two
ovarian cancer cell lines (A2780, OAW42) and one
osteogenic sarcoma cell line (U2-OS) and their sublines (A2780Cp8, OAW42-MER and U2-OS-R) with experimentally induced resistance to
cisplatin. A 1-h exposure to
C1311 significantly inhibited the growth of all cell lines, with IC50 values ranging from 0.50 +/-0.11 to 4.10+/-0.36 microM. No or only partial cross-resistance was found between
C1311 and
cisplatin in the different cell lines. Treatment with equitoxic (IC50)
C1311 concentrations consistently induced accumulation of cells in the G2M phase. The
cyclin B1-associated p34(cdc2)
kinase activity in cells arrested in G2M was superimposable to that of control cells in the OAW42-MER and U2-OS cell lines, whereas a reduction of cdc2 catalytic activity was observed in OAW42 and U2-OS-R cells. Exposure to
C1311 (IC50) induced apoptosis in the U2-OS and U2-OS-R cell lines, whereas in the OAW42 and OAW42-MER cell lines there was a negligible percentage of apoptotic cells. In U2-OS, U2-OS-R and OAW42 cells,
C1311 induced an increase in p53 expression and an increase in p21waf1
protein, whereas p53 failed to transactivate p21waf1 in OAW42-MER cells. An almost complete abrogation of bcl-2 was observed in U2-OS-R cells in correspondence with the peak of apoptosis induction. Our results indicate that
C1311 is active against human
ovarian cancer and
osteogenic sarcoma cells and is not cross-resistant with CDDP. Moreover,
C1311 blocks cells in the G2M phase and induces apoptosis in a small percentage of
osteogenic sarcoma cells.