Conclusions
Gö6976, when added to caffeine at doses below that required for cell-cycle over-ride, augments caffeine in overcoming CDDP resistance in this experimental system. G2/M over-ride is not the mechanism underlying the inhibition of proliferation. An AKT-independent apoptotic mechanism may be responsible.
Methods
We investigated the effects of caffeine and Gö6976 in the presence of CDDP in the SKOV3 and A2780 cell lines using proliferation, cell-cycle analysis, apoptosis, and AKT expression.
Results
Proliferation of cancer cells was decreased in a dose-dependent manner with caffeine and CDDP, but doses of caffeine required for significant inhibition were higher than that achievable in patients. Gö6976, a global PKC inhibitor with G2/M over-ride capability similar to caffeine, when combined with caffeine and CDDP at doses below that required for cell-cycle over-ride produced the growth inhibitory effects of a ten-fold higher caffeine concentration in both cell lines. CDDP induced G2/M arrest was significantly abrogated by caffeine but not by Gö6976 alone and no additional effect was seen on G2/M over-ride by the addition of Gö6976 to caffeine. Addition of Gö6976 to caffeine and CDDP did increase apoptosis but without altering phospho-AKT. Conclusions: Gö6976, when added to caffeine at doses below that required for cell-cycle over-ride, augments caffeine in overcoming CDDP resistance in this experimental system. G2/M over-ride is not the mechanism underlying the inhibition of proliferation. An AKT-independent apoptotic mechanism may be responsible.