Antitumor properties of salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and in vivo: Involvement of p38 MAPK activation

In order to search for alternative agents to overcome chemoresistance during the treatment of ovarian cancer, this study aimed to examine the anticancer effects and action mechanism of salinomycin, a selective inhibitor of cancer stem cells, on cisplatin-resistant human ovarian cancer cell lines in vitro and in vivo. The concentration- (0.01-200 mu M) and time-dependent (24-72 h) growth inhibitory effects of salinomycin were observed in the ovarian cancer cell lines OV2008, C13, A2780, A2780-cp, SKOV3 and OVCAR3, by measuring cell viability using the resazurin reduction assay. The IC50 (24 h) range of salinomycin on the six cell lines was found to be 1.7-7.4 mu M. After cisplatin-resistant C13 cells were treated with salinomycin, the percentage of apoptotic cells determined by flow cytometry was significantly increased, in a concentration- and time-dependent manner. However, no cell cycle arrest was detected in the G1/G0, S and G2/M phases in the salinomycin-treated and control cells. The Bio-Plex phosphoprotein 5-plex assay (Akt, I kappa B-alpha, ERK1/2, JNK and p38 MAPK) demonstrated a marked time- and concentration-dependent increase in the phosphorylation of p38 MAPK, subsequent to salinomycin treatment. Moreover, salinomycin significantly suppressed tumor growth in a tumor xenograft model. These findings suggested that salinomycin efficiently inhibits the cisplatin-resistant human ovarian cancer cell line growth through the induction of apoptosis, potentially associated with the p38 MAPK activation.