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.
Highlights
Radiation therapy is a standard treatment for localized prostate cancer and is commonly used in combination with androgen deprivation therapy (ADT) to enhance disease control rates [1]
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)
The early-responding elements of DNA damage-repair pathway were studied to determine whether ENZ alters the initial factors involved in recognition and signaling of DNA damage
Summary
Radiation therapy is a standard treatment for localized prostate cancer and is commonly used in combination with androgen deprivation therapy (ADT) to enhance disease control rates [1]. Local control is not achieved in nearly half of these cases, allowing the development of metastatic disease and nearly 30,000 deaths per year in the USA.[2] there is an urgent need for novel strategies that selectively sensitize prostate tumors and counteract resistance to radiation treatment. ADT, known as hormone therapy, for prostate cancer acts as a radiation sensitizer, enhancing the efficacy of radiation treatment. Several radiosensitization mechanisms for ADT have been implicated, most prominently the influence of androgen receptor (AR) activity on cell cycle checkpoint inhibition [3] and DNA damage repair pathway factors, which include.
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