Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Cancers

Raymond J. Andersen¹  Jon K. Obst²  Yukiyoshi Hirayama²  Marianne D. Sadar²  Teresa Tam²  Carmen A. Banuelos²  Amy H. Tien²  Nasrin R. Mawji²  Jacky K. Leung²  Jun Wang²  Yusuke Ito² 

[1] Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada;Department of Genome Sciences, British Columbia Cancer, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada;

关键词: prostate cancer;    DNA repair;    AR-V7;    ralaniten;    EPI-002;    enzalutamide;   

DOI  :  10.3390/cancers12071991

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown