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Novel effect of antihelminthic niclosamide on S100A4-mediated metastatic progression in colon cancer

Item Type:Article
Title:Novel effect of antihelminthic niclosamide on S100A4-mediated metastatic progression in colon cancer
Creators Name:Sack, U. and Walther, W. and Scudiero, D. and Selby, M. and Kobelt, D. and Lemm, M. and Fichtner, I. and Schlag, P.M. and Shoemaker, R.H. and Stein, U.
Abstract:Background: Metastasis formation in colon cancer severely reduces the survival rate in patients. S100A4, a calcium-binding protein, is implicated in promoting metastasis formation in colon cancer. Methods: To identify a transcription inhibitor of S100A4, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a S100A4 promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 muM niclosamide to analyze the effect on S100A4 mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. Results: Reduced S100A4 mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). Conclusion: Niclosamide inhibits S100A4-induced metastasis formation in a mouse model of colon cancer and has therapeutic potential.
Keywords:Anthelmintics, Antineoplastic Agents, beta Catenin, Biological Tumor Markers, Cell Movement, Cell Proliferation, Chromatin Immunoprecipitation, Colonic Neoplasms, Disease Progression, Electrophoretic Mobility Shift Assay, Immunoblotting, Inbred NOD Mice, Kaplan-Meier Estimate, Liver Neoplasms, Messenger RNA, Neoplasm Invasiveness, Neoplasm RNA, Neoplastic Gene Expression Regulation, Niclosamide, Parenteral Infusions, Prognosis, Random Allocation, Reverse Transcriptase Polymerase Chain Reaction, S100 Proteins, SCID Mice, Signal Transduction, Time Factors, Heterologous Transplantation, Tumor Cell Line, Tumor Stem Cell Assay, Wnt Proteins, Animals, Mice
Source:Journal of the National Cancer Institute
Publisher:Oxford University Press
Page Range:1018-1036
Date:6 July 2011
Additional Information:Erratum in: JNCI J Natl Cancer Inst (2011) 103 (13): 989. doi: 10.1093/jnci/djr255
Official Publication:https://doi.org/10.1093/jnci/djr190
PubMed:View item in PubMed

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