In vitro study of combined cilengitide and radiation treatment in breast cancer cell lines

Radiation Oncology

Arnab Chakravarti³  Julia White⁴  Wei Meng³  Alexander Huebner³  Ahmed Ibrahim²  Bin Li³  David Peereboom¹  James Perry³  Tim Lautenschlaeger³ 

[1] Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA;Pharmaceutical Industries Division, National Research Center, Cairo, Dokki 12622, Egypt;Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA;Department of Radiation Oncology, The Ohio State University, Columbus, OH 43210, USA

关键词: Radiation;    Brain metastasis;    Breast cancer;    Cilengitide;   

Others  :  1152664
DOI  :  10.1186/1748-717X-8-246

 received in 2013-08-06, accepted in 2013-10-18,  发布年份 2013

【 摘 要 】

Background

Brain metastasis from breast cancer poses a major clinical challenge. Integrins play a role in regulating adhesion, growth, motility, and survival, and have been shown to be critical for metastatic growth in the brain in preclinical models. Cilengitide, an αvβ3/αvβ5 integrin inhibitor, has previously been studied as an anti-cancer drug in various tumor types. Previous studies have shown additive effects of cilengitide and radiation in lung cancer and glioblastoma cell lines. The ability of cilengitide to enhance the effects of radiation was examined preclinically in the setting of breast cancer to assess its possible efficacy in the setting of brain metastasis from breast cancer.

Methods

Our panel of breast cells was composed of four cell lines: T-47D (ER/PR+, Her2-, luminal A), MCF-7 (ER/PR+, Her2-, luminal A), MDA-MB-231 (TNBC, basal B), MDA-MB-468 (TNBC, basal A). The presence of cilengitide targets, β3 and β5 integrin, was first determined. Cell detachment was determined by cell counting, cell proliferation was determined by MTS proliferation assay, and apoptosis was measured by Annexin V staining and flow cytometry. The efficacy of cilengitide treatment alone was analyzed, followed by assessment of combined cilengitide and radiation treatment. Integrin β3 knockdown was performed, followed by cilengitide and radiation treatment to test for incomplete target inhibition by cilengitide, in high β3 expressing cells.

Results

We observed that all cell lines examined expressed both β3 and β5 integrin and that cilengitide was able to induce cell detachment and reduced proliferation in our panel. Annexin V assays revealed that a portion of these effects was due to cilengitide-induced apoptosis. Combined treatment with cilengitide and radiation served to further reduce proliferation compared to either treatment alone. Following β3 integrin knockdown, radiosensitization in combination with cilengitide was observed in a previously non-responsive cell line (MDA-MB-231). Clonogenic assays suggested little radiosensitization effects of cilengitide.

Conclusions

Cilengitide appears to enhance radiation response in preclinical models of breast cancer. These data suggest that the combination of radiation therapy and cilengitide may prove to be effective where radiation is utilized for the treatment of gross disease in breast cancer, such as in the setting of brain metastasis.

【 授权许可】

   
2013 Lautenschlaeger et al.; licensee BioMed Central Ltd.

【 图 表 】

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