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PLoS One. 2019 Apr 1;14(4):e0214670. doi: 10.1371/journal.pone.0214670. eCollection 2019.

Radiosensitization by enzalutamide for human prostate cancer is mediated through the DNA damage repair pathway.

Author information

1
Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Abstract

Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.

PMID:
30933998
PMCID:
PMC6443157
DOI:
10.1371/journal.pone.0214670
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Astellas Pharma Global Development Inc funded the project. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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