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Published on: February 20, 2018
Novel guanide-substituted compounds bind to CXCR4 and inhibit breast cancer metastasis
Joyce B Shepard1, Royce A Wilkinson, Jean R Starkey
1Departments of aChemistry and Biochemistry bMicrobiology, Montana State University, Bozeman, Montana, USA.
Abstract:
CXCR4 has been shown to be overexpressed on breast cancer cells including the human MDA-MB-231 cell line. Cancer cells overexpressing the CXCR4 receptor are capable of undergoing metastasis to organs expressing high levels of CXCL12. We have synthesized numerous guanide, biguanide, phenylguanide, and naphthylguanide compounds that bind to CXCR4 at the CXCL12-binding site and thus should prevent CXCR4-facilitated cancer metastasis. The novel compounds presented here were tested for CXCR4 affinity, toxicity, receptor activation, and for their ability to prevent breast cancer metastases. Three of the compounds bound to CXCR4 at IC50 values of 0.06-0.2 μmol/l, with no associated cell toxicity or receptor activation at these concentrations. These high CXCR4 affinity compounds also showed inhibition of in-vitro wound migration. They were then tested in an in-vivo mouse breast cancer lung colony model. All of these compounds showed reductions in the number of MDA-MB-231 lung metastases compared with mock-treated control mice without evidence of cardiac, liver, or kidney toxicity in treated mice.
Insights
Novel guanide compounds targeting the CXCR4 receptor effectively inhibited breast cancer metastasis in preclinical models. These compounds show promise for preventing cancer spread without significant toxicity.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- CXCR4 receptor is overexpressed on breast cancer cells, promoting metastasis.
- Cancer cell metastasis is facilitated by the interaction between CXCR4 and CXCL12.
Purpose of the Study:
- To synthesize and evaluate novel guanide, biguanide, phenylguanide, and naphthylguanide compounds.
- To assess these compounds' ability to inhibit CXCR4-mediated breast cancer metastasis.
Main Methods:
- Compounds were tested for CXCR4 affinity, toxicity, and receptor activation.
- In vitro assays measured wound migration inhibition.
- An in vivo mouse model assessed the reduction of lung metastases.
Main Results:
- Three novel compounds demonstrated high affinity for CXCR4 (IC50 0.06-0.2 μmol/l) without toxicity or receptor activation.
- These compounds inhibited in vitro wound migration of cancer cells.
- In vivo studies showed significant reduction in lung metastases in a mouse model.
Conclusions:
- Novel guanide-based compounds effectively target CXCR4 and inhibit breast cancer metastasis.
- These compounds represent a promising therapeutic strategy for preventing cancer spread.
- Preclinical evaluation indicates a favorable safety profile with no observed organ toxicity.
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