Ivermectin Augments the In Vitro and In Vivo Efficacy of Cisplatin in Epithelial Ovarian Cancer by Suppressing Akt/mTOR Signaling

Abstract

BackgroundThe poor outcomes in epithelial ovarian cancer necessitate new treatments. In this work, we systematically analyzed the inhibitory effects of ivermectin and the molecular mechanism of its action in ovarian cancer. MethodsThe effects of ivermectin alone and its combination with cisplatin on growth and survival were examined using cultured ovarian cancer cells and a xenograft mouse model. The molecular mechanism of action of ivermectin, focusing on Akt/mTOR signaling, was elucidated. ResultsIvermectin arrested growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer, regardless of specific cellular and molecular differences. Ivermectin significantly augmented the inhibitory effect of cisplatin on ovarian cancer cells in a dose-dependent manner. Mechanistically, ivermectin suppressed the phosphorylation of key molecules in the Akt/mTOR signaling pathway in ovarian cancer cells. In addition, overexpression of constitutively active Akt restored ivermectin-induced inhibition of Akt/mTOR, growth arrest and apoptosis. In an ovarian cancer xenograft mouse model, ivermectin alone significantly inhibited tumor growth. In combination with cisplatin, tumor growth was completely reversed over the entire duration of drug treatment without any toxicity. Furthermore, the concentrations of ivermectin used in our study are pharmacologically achievable. ConclusionsOur work suggests that ivermectin may be a useful addition to the treatment armamentarium for ovarian cancer and that targeting Akt/mTOR signaling is a therapeutic strategy to increase chemosensitivity in ovarian cancer.