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Niclosamide for the treatment of cancer metastasis

a cancer metastasis and niclosamide technology, applied in the field of niclosamide, can solve the problems of aggressive tumor growth, difficult or impossible adjuvant treatment, difficult or impossible detection of metastatic lesions, etc., and achieve the effect of inhibiting s100a4-induced metastasis, inhibiting s100a4-induced metastasis formation, and reducing liver metastasis scor

Inactive Publication Date: 2014-10-02
UNITED STATES OF AMERICA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a composition called niclosamide that has benefits in treating cancer, specifically reducing the movement and invasion of cancer cells. The treatment is safe and effective in animals, including humans. The patent shows that niclosamide reduced the movement rate and inhibited the invasion of cancer cells in laboratory settings. This suggests that it could be a beneficial treatment for cancer metastasis, or the spread of cancer cells to other parts of the body. The patent also explains the mechanisms by which niclosamide may act to inhibit cancer cell movement.

Problems solved by technology

However, clinical outcome parameters in particularly in the metastatic situation, have changed only moderately.
Primary tumours can normally be removed by surgery but widely metastatic lesions are difficult to detect and difficult or impossible to treat with adjuvant therapies.
Nuclear β-catenin accumulation has been associated with late stages of tumor progression and development of metastases, and the presence of mutated β-catenin is associated with aggressive tumor growth and poor prognosis.
Increased expression of S100A4 is strongly associated with aggressiveness of a tumor, its ability to metastasize and poor survival in patients.
But, when S100A4 transgenic mice are crossed with mice demonstrating spontaneous tumor formation, it leads to aggressive tumor growth and metastasis.

Method used

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  • Niclosamide for the treatment of cancer metastasis
  • Niclosamide for the treatment of cancer metastasis
  • Niclosamide for the treatment of cancer metastasis

Examples

Experimental program
Comparison scheme
Effect test

example 1

High-Throughput Screening for S100A4 Inhibitors

[0084]HCT116-S100A4p-LUC colon cancer cells stably expressing a human S100A4 promoter-driven luciferase reporter gene construct were screened with the Library of Pharmacologically Active Compounds (LOPAC; FIG. 1, A). The LOPAC Library represents a collection of 1280 well characterized small molecule inhibitors. In a primary 4-concentration screen, 34 compounds were found to inhibit S100A4 promoter-driven luciferase expression by greater than 50% compared with DMSO-treated control cells (FIG. 1, B). In parallel, cell viability was determined using the Alamar blue assay to evaluate whether some of the inhibitory effects were caused by cytotoxicity (data not shown). Of the 34 effective compounds, 11 compounds most efficiently inhibited reporter gene expression at concentrations that were non-toxic or only slightly affected cell viability. To confirm the inhibitory capacity of the selected compounds and to more accurately establish the conc...

example 2

Effect of Niclosamide on S100A4 mRNA and Protein Expression

[0085]To determine an applicable niclosamide concentration, the cytotoxicity of niclosamide on HCT116 cells was analyzed. Exposure of HCT116 cells to increasing concentrations of niclosamide reduced cell viability in a concentration-dependent manner (EC50=2.2 μM; 95% Cl 1.87 to 2.92 μM) (FIG. 2, A). Choosing a concentration range from 0.1 μM to 2.5 μM niclosamide endogenous S100A4 expression in HCT116 cells was analyzed and found S100A4 mRNA and protein levels to be reduced in a concentration-dependent manner (FIG. 2, B). Concentrations of more than 0.5 μM niclosamide reduced the endogenous S100A4 mRNA amount to less than 50% of the solvent-treated control (control vs niclosamide, 1 μM mean 47.4%, 95% Cl 39.3% to 55.4%; P<0.01, 1.5 μM mean 39.2%, 95% Cl 11.4% to 89.7%; P<0.01, 2 μM mean 39.1, 95% Cl 18.3% to 59.9%, P<0.01, 2.5 μM mean 36.7%, 95% Cl 18.6% to 54.8%; P<0.001). Similar effects were observed at the S100A4 protein...

example 3

Effect of Niclosamide on S100A4-Induced Cell Migration and Invasion

[0088]S100A4 is a main regulator of cell motility (25). Thus, the effect of niclosamide on S100A4-induced cell migration in HCT116-vector and HCT116-S100A4 cells was analyzed. The number of migrated cells was inhibited in HCT116-vector cells in the presence of niclosamide (control vs niclosamide, mean 100.0% vs 43.0%, mean difference 57.0%, 95% Cl 40.3% to 73.7%, P<0.0001) (FIG. 3, A). In contrast, migration rates of HCT116-S100A4 cells showed no reduction upon niclosamide treatment (control vs niclosamide, mean 145.0% vs 117.0%, mean difference 28%, 95% Cl −7.8% to 63.9%, statistically not significant).

[0089]The invasion rates of HCT116-vector and HCT116-S100A4 cells were also determined, since S100A4 is well known to stimulate cell invasion (11). The number of invaded cells was decreased in niclosamide-treated HCT116-vector cells (control vs niclosamide, mean 100% vs 30.1%, mean difference 69.9%, 95% Cl 10.9% to 12...

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Abstract

The invention relates to niclosamide and derivates thereof, which effectively inhibit transcription of the S100A4 gene, resulting in inhibition and / or reduction of S100A4-induced cell motility, invasiveness, metastasis and proliferation of human cancer cells.

Description

FIELD OF INVENTION[0001]Cancer metastasis is often associated with activation of the Wnt / β-catenin signaling pathway and high expression of the metastasis-inducing gene S100A4. It has been demonstrated in the state of the art, that S100A4 is transcriptionally regulated by β-catenin and that this is important for colon cancer and metastasis. The invention relates to niclosamide and derivates thereof, which effectively inhibit transcription of the S100A4 gene, resulting in inhibition of S100A4-induced cell motility, invasiveness, metastasis and proliferation of human cancer cells.BACKGROUND OF THE INVENTION[0002]Over the last decades, the efficacy of cancer treatment has improved considerably. However, clinical outcome parameters in particularly in the metastatic situation, have changed only moderately. Therefore, the development of new approaches to fight cancer is the ultimate goal of scientists as well as of pharmaceutical companies.[0003]Colorectal cancer is one of the most freque...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/167
CPCA61K31/167A61K31/4035A61K45/06A61P35/00
Inventor STEIN, ULRIKEWALTHER, WOLFGANGSACK, ULRIKESHOEMAKER, ROBERTSCUDIERO, DOMINICSCHLAG, PETER M
Owner UNITED STATES OF AMERICA
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