Comparison of the effects of valproic acid and levetiracetam on apoptosis in the human ovarian cancer cell ine OVCAR-3.

摘要

Background: We have previously shown that due to its cytotoxic and cytostatic activities, valproic acid (VPA), but not leveti- racetam (LEV), may have potential as a drug for treating human ovarian cancer. In the present study, we compare apoptotic mecha- nisms including gene and protein expression in the human ovarian cancer cell line, OVCAR-3, following exposure to VPAand LEV. Methods: Cells were cultured with VPA or LEV at concentrations between 0.1 mM and 10 mM. Apoptosis was assessed by DNA fragmentation assay and expression of apoptosis-regulatory genes determined by real-time PCR and confirmed by western blotting. Time-dependent effects of VPA and LEV on activity of caspases (-3, -8 and -9) activity were evaluated by fluorescent assay and western blotting. Results: Exposure to VPA at concentrations above 5 mM resulted in an increase in DNA fragmentation, modulated expression of genes and proteins associated with apoptosis and activated caspases ca scade. Exposure to LEV, however, did not affect DNAfrag- mentation and modulation of the mechanisms of apoptosis was not observed in LEV-treated cells at all doses used. Conclusions: Exposure to high concentrations of VPAsignificantly stimulated apoptosis, by modulating the expression of genes and proteins responsible for cell death and also by activation of caspases cascade. Such effects were not observed with LEV. These data suggest that VPA should be seriously evaluated as an anti-cancer drug for ovarian cancer.