马拉维若阻断 CCR5：转移性乳腺癌的潜在治疗选择。
CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer.
机构信息
Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
Toxicology and Chemotherapy Unit, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
出版信息
Cell Oncol (Dordr). 2019 Feb;42(1):93-106. doi: 10.1007/s13402-018-0415-3. Epub 2018 Nov 19.
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.
目的
多达 70%的乳腺癌患者会发生骨转移。目前可用的治疗方法本质上是姑息性的。趋化因子受体 5（CCR5）作为各种恶性肿瘤的治疗靶点引起了关注。在这里，我们研究了用其拮抗剂马拉维若治疗转移性乳腺癌细胞中 CCR5 的效果。
方法
用 MTT 增殖测定法评估马罗维罗暴露后的细胞毒性，用集落形成、Transwell 室迁移和划痕愈合测定法分别评估对集落形成和迁移的影响。用核染色、Annexin-V FITC 染色和 Western blot 研究细胞凋亡相关活性。用流式细胞术和 qRT-PCR 分析细胞周期变化，以检测细胞周期相关基因。使用裸鼠乳腺癌骨转移模型评估马罗维罗靶向 CCR5 的体内疗效。用 ELISA 分析乳腺癌患者血清中 CCR5 的三个同源配体（CCL3、CCL4、CCL5）的循环水平。
结果
我们发现阻断 CCR5 可减弱转移性乳腺癌细胞的增殖、集落形成和迁移，并诱导细胞凋亡和细胞周期 G1 期阻滞。表达谱突出了细胞周期相关信号通路的参与。我们还发现，用马罗维罗治疗可显著抑制 MDA-MB-231 乳腺癌细胞植入裸鼠的骨转移。最后，我们发现 CCR5 受体的三个同源配体的循环水平在乳腺癌患者和健康对照者之间存在差异。
结论
我们的研究结果表明，靶向 CCR5 可能是治疗乳腺癌骨转移的有效策略。
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