Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin-resistant human epidermal growth factor receptor 2-positive breast cancer.

Abstract

Chemotherapy-resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial-mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem-like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple-negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial-to-mesenchymal transition, as well as the stem-like phenotype in cisplatin-resistant HER2-positive breast cancer. Alamar Blue and Annexin V/7-AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem-like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2-positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial-mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl-2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2-positive breast cancer.