Niclosamide for the treatment of cancer metastasis

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...

AI Technical Summary

Benefits of technology

[0098]Next, the effect of niclosamide on metastasis formation in xenograft mice by non-invasive in vivo luminescence imaging was monitored. On day 8 after intrasplenic transplantation of HCT116-CMVp-LUC cells, stably expressing firefly luciferase, a visible spleen tumor has formed in solvent-treated control mice and in 20 mg per kg niclosamide-treated mice (FIG. 7, A). Lateral imaging showed that the spleen tumor signal increased in solvent and niclosamide-treated mice until it reached a maximum on day 24. Differences in signal localization were found by ventral imaging. In control mice a liver metastasis signal could be detected which was confirmed by in situ imaging and isolation of liver and spleen. No or only tiny liver metastasis signals could be detected in niclosamide-treated mice.

[0099]Niclosamide was able to inhibit S100A4 expression in vivo, since S100A4 mRNA levels were reduced in niclosamide-treated mice (control vs 2×15 mg per kg, mean 100.0% vs 58.4%, mean difference 41.7%, 95% Cl 21.6% to 61.8%, P<0.001; control vs 20 mg per kg, mean 100.0% vs 67.2%, mean difference 32.9%, 95% Cl 14.1% to 51.7%, P<0.001) (FIG. 7, B). Liver metastasis score was diminished in niclosamide-treated mice compared with solvent-treated mice (control mean 100.0%, 95% Cl −15.4% to 215.4%; 2×15 mg per kg mean 36.1%, 95% Cl 12.4% to 59.8%; 20 mg per kg mean 37.9%, 95% Cl 22.6% to 53.1%) (FIG. 7, C). In summary, it was concluded that niclosamide treatment inhibits S100A4-induced metastasis formation in vivo.

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.

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