Activity of cisplatin and ICI 182,780 on estrogen receptor negative ovarian cancer cells: Cell cycle and cell replication rate perturbation, chromatin texture alteration and apoptosis induction

The activity of cisplatin (CP, range of concentrations 0.25-1 μg/ml), the pure steroidal antiestrogen compound ICI 182,780 (range of concentrations, 0.01-10 μM) and various combinations of, was investigated on an estrogen receptor negative ovarian cancer cell line (A2780 WT) and its CP- resistant derivative subline (A2780 CP3). CP markedly reduced A2780 WT cell growth but marginally affected A2780 CP3, whereas ICI 182,780 was effective on both cell lines. CP but not ICI 182,780 provoked a significant blockade in late S/G₂ phase in both cell lines, particularly in the parental line. Measuring the number of rounds of cell replications showed that CP diminished the cell replication rate of both cell lines, particularly in A2780 WT. Conversely, ICI 182,780 reduced the cell replication rate of A2780 CP3 but not A2780 WT cells. Both drugs provoked apoptosis in A2780 WT cells, as assessed by the appearance of large (50-300 kbp) DNA fragmentation. However, laser scanning cytometry showed that only CP induced a measurable alteration of chromatin texture in A2780 WT but not in A2780 CP3 cells. The combination CP and ICI 182,780 resulted in a synergistic inhibitory activity of cell growth with a CP potentiation up to 4 and 11-fold in A2780 WT and A2780 CP3 cells, respectively. This reflected an enhanced reduction of the cell replication rate and did not involve perturbations of the cell cycle other than those provoked by CP alone. Apoptosis induction and the level of CP-DNA adducts were not influenced by adding ICI 182,780 to CP in both cell lines.