Niclosamide and Pyrvinium Are Both Potential Therapeutics for Osteosarcoma, Inhibiting Wnt–Axin2–Snail Cascade

SIMPLE SUMMARY: Epithelial–mesenchymal transition (EMT) regulated by Wnt signaling is known as a key mechanism of cancer progression. Although evidence has suggested that the oncogenic Wnt signaling pathway and EMT program are important in the progression of osteosarcoma, there is no known therapeutic drug targeting EMT for osteosarcoma. We investigated whether Axin2, an important EMT target, could be a suitable molecular target and biomarker for osteosarcoma. Furthermore, we showed that both niclosamide and pyrvinium target Axin2, and effectively induce EMT reversion in osteosarcoma cell lines. Our findings suggest an effective biomarker and potential EMT therapeutics for osteosarcoma patients. ABSTRACT: Osteosarcoma, the most common primary bone malignancy, is typically related to growth spurts during adolescence. Prognosis is very poor for patients with metastatic or recurrent osteosarcoma, with survival rates of only 20–30%. Epithelial–mesenchymal transition (EMT) is a cellular mechanism that contributes to the invasion and metastasis of cancer cells, and Wnt signaling activates the EMT program by stabilizing Snail and β-catenin in tandem. Although the Wnt/Snail axis is known to play significant roles in the progression of osteosarcoma, and the anthelmintic agents, niclosamide and pyrvinium, have been studied as inhibitors of the Wnt pathway, their therapeutic effects and regulatory mechanisms in osteosarcoma remain unidentified. In this study, we show that both niclosamide and pyrvinium target Axin2, resulting in the suppression of EMT by the inhibition of the Wnt/Snail axis in osteosarcoma cells. Axin2 and Snail are abundant in patient samples and cell lines of osteosarcoma. The treatment of niclosamide and pyrvinium inhibits the migration of osteosarcoma cells at nanomolar concentrations. These results suggest that Axin2 and Snail are candidate therapeutic targets in osteosarcoma, and that anthelminthic agents, niclosamide and pyrvinium, may be effective for osteosarcoma patients.