Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
department or school: Medicine, Faculty of
department or school: Science, Faculty of
department or school: Non UBC
department or school: Chemistry, Department of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
identifier citation: Cancers 12 (7): 1991 (2020)
creator: Banuelos, Carmen A.
creator: Ito, Yusuke
creator: Obst, Jon K.
creator: Mawji, Nasrin R.
creator: Wang, Jun
creator: Hirayama, Yukiyoshi
creator: Leung, Jacky K.
creator: Tam, Teresa
creator: Tien, Amy H.
creator: Andersen, Raymond J.
creator: Sadar, Marianne D.
issued: 2020-07-24T21:17:46Z
issued: 2020-07-21
description: 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.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/75269
note: cancersArticleRalaniten Sensitizes Enzalutamide-Resistant ProstateCancer to Ionizing Radiation in Prostate Cancer Cellsthat Express Androgen Receptor Splice VariantsCarmen A. Banuelos 1, Yusuke Ito 1, Jon K. Obst 1, Nasrin R. Mawji 1, Jun Wang 1,Yukiyoshi Hirayama 1, Jacky K. Leung 1, Teresa Tam 1, Amy H. Tien 1, Raymond J. Andersen 2 andMarianne D. Sadar 1,3,*1 Department of Genome Sciences, British Columbia Cancer, 675 West 10th Avenue,Vancouver, BC V5Z 1L3, Canada; abanuelos@bcgsc.ca (C.A.B.); yitou1@yokohama-cu.ac.jp (Y.I.);jobst@bcgsc.ca (J.K.O.); nmawji@bcgsc.ca (N.R.M.); jeanwang@bcgsc.ca (J.W.); ukiyoc@gmail.com (Y.H.);jleung@bcgsc.ca (J.K.L.); ttam@bcgsc.ca (T.T.); atien@bcgsc.ca (A.H.T.)2 Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada;raymond.andersen@ubc.ca3 Department of Pathology and Laboratory Medicine, University of British Columbia,Vancouver, BC V6T 1Z7, Canada* Correspondence: msadar@bcgsc.ca; Tel.: +604-675-8157; Fax: +604-675-8178Received: 17 June 2020; Accepted: 17 July 2020; Published: 21 July 2020Abstract: 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 splicevariants 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-Vswith ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralanitenwith ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNAdamage, and Western blot analyses in human prostate cancer cells that express both full-lengthAR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression ofDNA repair genes whereas enzalutamide had no effect. FACS…
has type: Article
is shown at: 10.14288/1.0392543
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: Multidisciplinary Digital Publishing Institute
publisher DOI: 10.3390/cancers12071991
rights: CC BY 4.0
rights URI: https://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
scholar level: Other
subject: prostate cancer
subject: DNA repair
subject: AR-V7
subject: ralaniten
subject: EPI-002
subject: enzalutamide
subject: radiotherapy
type: Text
identifier URI: http://hdl.handle.net/2429/75269