CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer
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Bone metastasis is observed in up to 70% of breast cancer patients. The currently available treatment options are palliative in nature. Chemokine receptor 5 (CCR5) has gained attention as therapeutic target in various malignancies. Here, we investigated the effects of targeting CCR5 by its antagonist maraviroc in metastatic breast cancer cells.
In response to maraviroc exposure, cytotoxicity was assessed using an MTT proliferation assay, whereas the effects on colony formation and migration were assessed using colony formation, transwell chamber migration and scratch wound healing assays, respectively. Apoptosis-related activities were investigated using nuclear staining, annexin-V FITC staining and Western blotting. Cell cycle changes were analysed using flow cytometry and qRT-PCR for cell cycle relevant genes. A nude rat model for breast cancer bone metastasis was used to evaluate the in vivo efficacy of CCR5 targeting by maraviroc. Circulatory levels of the three cognate ligands for CCR5 (CCL3, CCL4, CCL5) were analysed in sera of breast cancer patients using ELISA.
We found that blockade of CCR5 attenuated the proliferation, colony formation and migration of metastatic breast cancer cells, and induced apoptosis and arrest in the G1 phase of the cell cycle. Expression profiling highlighted the involvement of cell cycle related signalling cascades. We also found that treatment with maraviroc significantly inhibited bone metastasis in nude rats implanted with MDA-MB-231 breast cancer cells. Finally, we found that the circulatory levels of three cognate ligands for the CCR5 receptor varied between breast cancer patients and healthy controls.
Our findings indicate that targeting CCR5 may be an effective strategy to combat breast cancer bone metastasis.
KeywordsBreast cancer Bone metastasis CCR5 Maraviroc Cell cycle arrest Apoptosis
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
For clinical investigations, informed consent was obtained from all patients and the study was approved by the relevant authorities from University of Health Sciences and INMOL hospital, Lahore, Pakistan. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Animal experiments were approved by the author’s institutional review board and governmental animal ethics committee (Regierungspräsidium, Karlsruhe, Germany). All applicable international, national and/or institutional guidelines for the care and use of animals were followed.
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