Targeting of Wnt/?-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy.

ABSTRACT: BACKGROUND Aberrant activation of Wnt/?-catenin has been shown to promote ovarian cancer proliferation and chemoresistance. Pyrvinium, an FDA-approved anthelmintic drug, has been identified as a potent Wnt inhibitor. Pyrvinium may sensitize ovarian cancer cells to chemotherapy. MATERIAL AND METHODS The effect of pyrvinium alone and its combination with paclitaxel in ovarian cancer was investigated using an in vitro culture system and in vivo xenograft models. The mechanisms of its action were also analyzed, focusing on the Wnt/?-catenin pathway. RESULTS Pyrvinium inhibited growth and induced apoptosis of paclitaxel- and cisplatin-resistant epithelial ovarian cancer cell lines A2278/PTX and SK-OV-3. Its combination with paclitaxel was synergistic in targeting ovarian cancer cells in vitro. In 3 independent ovarian xenograft mouse models, pyrvinium alone inhibited tumor growth. More importantly, we observed significant inhibition of tumor growth throughout the treatment when using pyrvinium and paclitaxel combined. Mechanistically, pyrvinium increased the Wnt-negative regulator axin and decreased the b-catenin levels in ovarian cancer cells. In addition, pyrvinium suppressed Wnt/b-catenin-mediated transcription, as shown by the decreased mRNA levels of MYC, cyclin D, and BCL-9. In contrast, the inhibitory effects of pyrvinium were reversed by ?-catenin stabilization or overexpression, demonstrating that pyrvinium acted on ovarian cancer cells via targeting the Wnt/?-catenin signaling pathway. CONCLUSIONS We demonstrated that the anthelmintic drug pyrvinium targets ovarian cancer cells through suppressing Wnt/?-catenin signaling. Our work highlights the therapeutic value of inhibiting Wnt/?-catenin in ovarian cancer.

SUBMITTER: Zhang C 

PROVIDER: S-EPMC5266205 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature