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CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer
Asim Pervaiz1,2, Michael Zepp2, Saqib Mahmood1
1Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
Our findings indicate that targeting CCR5 may be an effective strategy to combat breast cancer bone metastasis.
Insights
Targeting chemokine receptor 5 (CCR5) with maraviroc reduced breast cancer cell growth, migration, and bone metastasis. This approach also induced cancer cell death and cell cycle arrest, suggesting CCR5 as a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Bone metastasis affects up to 70% of breast cancer patients, with current treatments offering palliative care.
- Chemokine receptor 5 (CCR5) is an emerging therapeutic target in various cancers.
- Targeting CCR5 presents a potential strategy to address limitations in breast cancer bone metastasis treatment.
Purpose of the Study:
- To investigate the efficacy of maraviroc, a CCR5 antagonist, in inhibiting metastatic breast cancer cells.
- To evaluate the effects of CCR5 blockade on cancer cell proliferation, colony formation, migration, apoptosis, and cell cycle.
- To assess the in vivo effectiveness of CCR5 targeting in a preclinical model of breast cancer bone metastasis.
Main Methods:
- Cytotoxicity and proliferation were assessed using MTT assays.
- Colony formation, migration, and wound healing assays evaluated cellular growth and motility.
- Apoptosis was analyzed via nuclear staining, annexin-V FITC, and Western blotting.
- Cell cycle progression was studied using flow cytometry and qRT-PCR.
- In vivo efficacy was tested in a nude rat model of breast cancer bone metastasis.
- Circulatory levels of CCR5 ligands (CCL3, CCL4, CCL5) were measured in patients using ELISA.
Main Results:
- CCR5 blockade with maraviroc significantly reduced breast cancer cell proliferation, colony formation, and migration.
- Maraviroc treatment induced apoptosis and G1 phase cell cycle arrest in cancer cells.
- In vivo studies demonstrated that maraviroc inhibited bone metastasis in a preclinical model.
- Circulatory levels of CCR5 ligands differed between breast cancer patients and healthy individuals.
Conclusions:
- Targeting CCR5 with maraviroc shows promise as an effective strategy against breast cancer bone metastasis.
- The findings highlight CCR5 as a potential therapeutic target for managing metastatic breast cancer.
- Further research into CCR5-targeted therapies could lead to improved treatment outcomes for patients with bone metastasis.
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