Niclosamide inhibits the cell proliferation and enhances the responsiveness of esophageal cancer cells to chemotherapeutic agents

Abstract

Niclosamide is an FDA-approved anthelmintic drug, and may elicit antineoplastic effects through direct STAT3 inhibition, which has been revealed in numerous human cancer cells. Chemotherapy is the standard treatment for advanced esophageal cancers, but also causes severe systemic side effects. The present study represents the first study evaluating the anticancer efficacy of niclosamide in esophageal cancers. Through western blot assay, it was demonstrated that niclosamide suppressed the STAT3 signaling pathway in esophageal adenocarcinoma cells (BE3) and esophageal squamous cell carcinoma cells (CE48T and CE81T). In addition, niclosamide inhibited cell proliferation as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and soft agar colony forming assay, and induced cell apoptosis as determined by Annexin V and PI staining. The induction of p21 and G1 arrest of the cell cycle also was revealed in niclosamide-treated CE81T cells by qPCR and flow cytometric assays, respectively. Furthermore, in the combination analysis of niclosamide and chemotherapeutic agents by MTS assay, low IC 50 values were detected in cells co-treated with niclosamide, with the exception of cisplatin-treated CE81T cells. To confirm the results using an apoptosis assay, the apoptotic enhancement of niclosamide was only demonstrated in CE48T cells co-treated with 5-FU, cisplatin, or paclitaxel, and in BE3 cells co-treated with paclitaxel, but not in CE81T cells. These findings indicate a future clinical application of niclosamide in esophageal cancers.

Molecular mechanism, regulation, and therapeutic targeting of the STAT3 signaling pathway in esophageal cancer (Review)

“…In addition, suppressing the activation of STAT3 was demonstrated to enhance the sensitivity to cisplatin ( 88 ). For commonly used chemotherapeutic drugs such as 5-fluorouracil (5-FU), cisplatin, and paclitaxel, the IC 50 values in EC cells were reduced when these drugs were combined with STAT3 inhibitors such as niclosamide ( 89 ). In addition to resistance to chemotherapy, STAT3 is involved in radioresistance as well.…”

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

“…222 Niclosamide is an antihelminthic drug that has also demonstrated anti-cancer effects on several types of human cancer cells. [223][224][225] It has been more extensively investigated in experimental and clinical studies for individuals suffering from prostate and colorectal cancer. 226,227 Apart from its anti-neoplastic effects, niclosamide also demonstrated to inhibit TMEM16A and other members of the TMEM16 family.…”

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

“…This effect resulted in the arrest of cells in the G0/G1 phase and induction of cell apoptosis [39]. Moreover, niclosamide potentiated the cytotoxic effects of some chemotherapeutic drugs, such as 5-FU, cisplatin and paclitaxel, thereby shifting their IC50 to lower doses with the ultimate result of reducing potential side effects in treated patients [39].…”

“…More recent studies showed a protective effect of niclosamide in esophageal cancer [ 39 ]. In particular, niclosamide (2.5–10 μM) suppressed the STAT3 signaling pathway in esophageal adenocarcinoma cells (BE3) and esophageal squamous cell carcinoma cells (CE48T and CE81T) by impairing both STAT3 phosphorylation on Y705 residue and STAT3 protein expression.…”

“…In particular, niclosamide (2.5–10 μM) suppressed the STAT3 signaling pathway in esophageal adenocarcinoma cells (BE3) and esophageal squamous cell carcinoma cells (CE48T and CE81T) by impairing both STAT3 phosphorylation on Y705 residue and STAT3 protein expression. This effect resulted in the arrest of cells in the G0/G1 phase and induction of cell apoptosis [ 39 ]. Moreover, niclosamide potentiated the cytotoxic effects of some chemotherapeutic drugs, such as 5-FU, cisplatin and paclitaxel, thereby shifting their IC50 to lower doses with the ultimate result of reducing potential side effects in treated patients [ 39 ].…”