Targeting Wnt/β-catenin by anthelmintic drug niclosamide overcomes paclitaxel resistance in esophageal cancer

Esophageal cancer is an aggressive malignancy, and its current treatment strategies are plagued with high rates of recurrence. In this work, we demonstrate that niclosamide, an anthelmintic drug, is a potential sensitizing candidate for overcoming chemoresistance in esophageal cancer. Using a panel of esophageal cancer cell lines and normal cells, we show that niclosamide has anti-esophageal cancer activity and is likely to be less effective against normal esophageal epithelial and fibroblast cells. The combination of niclosamide with paclitaxel results in much greater efficacy than paclitaxel alone, suggesting that niclosamide is active against esophageal cancer cells that are resistant to paclitaxel. This is further confirmed by our results that niclosamide is effective in inhibiting proliferation and inducing apoptosis in paclitaxel-resistant esophageal cancer cells. In line with the findings obtained from in vitro cell culture system, niclosamide augments the in vivo efficacy of paclitaxel and significantly arrests paclitaxel-resistant esophageal cancer growth without causing toxicity in mice. Mechanistically, we show that niclosamide decreases beta-catenin level and activity, and inhibits phosphorylation of STAT3 and mTORC1 substrate 70S6K. Stabilization of beta-catenin level by Wnt activator lithium chloride (LiCl) significantly abolishes the inhibitory effects of niclosamide in inhibiting proliferation and survival but not suppressing phosphorylation of STAT3 and 70S6K in paclitaxel-resistant esophageal cancer cells, suggesting that niclosamide sensitizes esophageal cancer cell to paclitaxel mainly through inhibiting Wnt/beta-catenin. Our work demonstrates the efficacy of niclosamide and its underlying mechanism in paclitaxel-resistant esophageal cancer. Our work emphasizes that Wnt/beta-catenin inhibition is a sensitizing strategy in esophageal cancer.

Automated summary

Esophageal cancer is a highly aggressive malignancy with high rates of recurrence. Niclosamide, an anthelmintic drug, shows potential as a sensitizing agent to overcome chemoresistance in esophageal cancer, particularly in combination with paclitaxel. Mechanistically, niclosamide inhibits Wnt/beta-catenin signaling and shows efficacy in inhibiting proliferation and inducing apoptosis in paclitaxel-resistant esophageal cancer cells.