Progesterone-calcitriol combination enhanced cytotoxicity of cisplatin in ovarian and endometrial cancer cells in vitro

Initially, patients that respond to cisplatin (DDP) treatment later relapse and develop chemoresistance. Agents that enhance DDP effectiveness will have a significant impact on cancer treatment. We have shown pronounced inhibitory effects of the progesterone-calcitriol combination on endometrial and ovarian cancer cell growth. Here, we examined whether and how progesterone-calcitriol combination potentiates DDP anti-tumor effects in cancer cells. Ovarian and endometrial cancer cells treated with various concentrations of DDP showed a concentration-dependent decrease in cell proliferation. Concurrent treatment of cells with DDP and progesterone-calcitriol ombination potentiated anticancer effects of DDP compared to DDP-calcitriol, or DDP-progesterone treated groups. The anticancer effects were mediated by increased caspase-3, BAX, and decreased BCL2 and PARP-1 expression in DDP and progesterone-calcitriol combination-treated cells. Stimulation of the PI3K/AKT and MAPK/ERK pathways seen in cancer cells was reduced in DDP-progesterone-calcitriol treated cells. Pretreatment of cells with specific inhibitors further diminished AKT and ERK expression. Furthermore, progesterone-calcitriol potentiated the anti-growth effects of DDP on cancer cells by attenuating the expression of SMAD2/3, multidrug resistance protein- 1 (MDR-1), and ABC transporters (ABCG1, and ABCG2), thereby impeding the effiux of chemo drugs from cancer cells. These results suggest a potential clinical benefit of progesterone-calcitriol combination therapy when used in combination with DDP.