Abstract
Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.
Highlights
Radiotherapy is one of the primary treatment options for localized prostate cancer and when combined with androgen deprivation therapy (ADT) there is significant improvement in disease-free and overall survival for intermediate and high-risk disease [1,2,3,4]
androgen receptor (AR) regulates the expression of many genes in prostate cells including those controlling cellular proliferation and survival thereby providing the rationale for ADT to block AR signaling as a systemic therapy for prostate cancer
AR transcriptional activity compared to ralaniten; (b) ralaniten and EPI-7170 decreased mRNA and protein expression of DNA damage repair (DDR) genes; and (c) a combination of ralaniten with ionizing radiation (IR) led to an accumulation of cells in S phase harboring increased DNA damage. These results reveal that blocking AR-N-terminal domain (NTD) to inhibit the transcriptional activities of both full-length AR and AR splice variants (AR-Vs) combined with IR provides a new opportunity for the treatment of prostate cancer
Summary
Radiotherapy is one of the primary treatment options for localized prostate cancer and when combined with androgen deprivation therapy (ADT) there is significant improvement in disease-free and overall survival for intermediate and high-risk disease [1,2,3,4]. AR transcriptional activity compared to ralaniten; (b) ralaniten and EPI-7170 decreased mRNA and protein expression of DDR genes; and (c) a combination of ralaniten with ionizing radiation (IR) led to an accumulation of cells in S phase harboring increased DNA damage. These results reveal that blocking AR-NTD to inhibit the transcriptional activities of both full-length AR and AR-Vs combined with IR provides a new opportunity for the treatment of prostate cancer. Cancers 2020, 12, x results reveal that blocking AR-NTD to inhibit the transcriptional activities of both full-length AR and AR-Vs combined with IR provides a new opportunity for the treatment of prostate cancer
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