Protein kinase C inhibitor Go6976 augments caffeine-induced reversal of chemoresistance to cis-diamminedichloroplatinum-II (CDDP) in a human ovarian cancer model.

摘要

OBJECTIVES: Novel strategies for the treatment of chemoresistant ovarian cancer are needed. Caffeine and related compounds have been shown to over-ride G2/M arrest in ovarian cancer cells, increasing toxicity to chemotherapy. Newer compounds have been developed which may have the same effect as and exhibit synergism with caffeine, allowing the use of lower doses. METHODS: We investigated the effects of caffeine and Go6976 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. Go6976, 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 Go6976 alone and no additional effect was seen on G2/M over-ride by the addition of Go6976 to caffeine. Addition of Go6976 to caffeine and CDDP did increase apoptosis but without altering phospho-AKT. CONCLUSIONS: Go6976, 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.