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CXCR4 inhibition enhances radiosensitivity, while inducing cancer cell mobilization in a prostate cancer mouse model

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Abstract

Preclinical studies show that stroma affects sensitivity of prostate cancer cells via activation of the CXCR4/CXCL12 pathway. Here we studied the effect of CXCR4 inhibition combined with irradiation in prostate cancer cells. In an in vitro co-culture with stromal cells, the CXCR4 inhibitor AMD3100 sensitized prostate cancer cell lines PC3-Luc and LNCaP to irradiation (P = 0.04). Tumor growth and metastasis were evaluated in mice xenografted with luciferase-expressing PC3 cells that received 5 Gy irradiation weekly ± 3.5 mg/kg AMD3100 daily intraperitoneally. The irradiated xenografts showed higher CXCR4 (P = 0.006) and CXCL12 (P = 0.01) expression, compared to controls. AMD3100 sensitized the xenografts to irradiation at the fourth week of treatment (P = 0.02). However AMD3100 also mobilized tumor cells at days 14 and 21 (P < 0.0001), as shown by bioluminescent imaging. In conclusion, AMD3100 transiently enhances prostate cancer radiosensitivity, but induces cancer cell mobilization.

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Acknowledgments

We thank Karin Tamas, Roeliene C. Kruizinga and Coby Meijer for inspiring comments and discussions and Malgorzata Krajewska for her support with FACS analysis of DNA damage. This study was supported by the Dutch Cancer Society (grant number RUG 2010-4622).

Conflict of interest

All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departments of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30.00, 19700 RB, Groningen, The Netherlands

    Urszula M. Domanska, Jennifer C. Boer, Hetty Timmer-Bosscha, Marcel A. T. M. van Vugt, Nathalie M. Kliphuis, Elisabeth G. E. de Vries & Annemiek M. E. Walenkamp

  2. Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Hilde D. Hoving & Igle Jan de Jong

  3. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Stefano Rosati

  4. Department of Urology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands

    Henk G. van der Poel

Authors
  1. Urszula M. Domanska
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Correspondence to Annemiek M. E. Walenkamp.

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Domanska, U.M., Boer, J.C., Timmer-Bosscha, H. et al. CXCR4 inhibition enhances radiosensitivity, while inducing cancer cell mobilization in a prostate cancer mouse model. Clin Exp Metastasis 31, 829–839 (2014). https://doi.org/10.1007/s10585-014-9673-2

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  • DOI: https://doi.org/10.1007/s10585-014-9673-2

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