Cisplatin is the most active agent in the
chemotherapy of
ovarian cancer and this activity can be enhanced by liposomal
valinomycin (MLV-VM) in vitro. To test whether MLV-VM is capable of augmenting the cytotoxic and cytokinetic effects of other
platinum analogs,
drug combinations of MLV-VM and
platinum drugs were tested against two human
ovarian cancer cell lines (OVCAR-3 and CaOV-3) and on Chinese hamster ovary (CHO) cells in vitro. MLV-VM enhanced the sensitivity to
cisplatin,
ormaplatin and
carboplatin on human ovarian
carcinoma cells that show various degrees of
drug sensitivity. This interaction was shown to be truly synergistic by median-effect analysis up to 90% cell kill. The combination index at 50% cell kill (Cl50) was also used to quantitate the extent of
drug synergy. In the OVCAR-3 cell line, for example, the Cl50s were 0.62, 0.85 and 0.8 for
cisplatin,
ormaplatin and
carboplatin, respectively.
DNA histograms obtained by flow cytometry showed that CHO cells treated with
cisplatin alone accumulated in the S-G2 segment, with a partial G2 block. The addition of 2 microM VM with
cisplatin, significantly enhanced the accumulation of cells at the G2/M phase. Our results further demonstrate that in vitro treatment with VM,
cisplatin and/or combination is associated with an increase in
protein kinase C (PKC) activity. These findings suggest that accumulation of cells at G2/M phases and modulation of PKC activity could be among the basis for the cytotoxic synergism observed between
cisplatin and VM.