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

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 (...

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Published inCancers Vol. 12; no. 7; p. 1991
Main Authors Banuelos, Carmen A., Ito, Yusuke, Obst, Jon K., Mawji, Nasrin R., Wang, Jun, Hirayama, Yukiyoshi, Leung, Jacky K., Tam, Teresa, Tien, Amy H., Andersen, Raymond J., Sadar, Marianne D.
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 21.07.2020
MDPI
Subjects
Alternative splicing
Androgen receptors
Androgens
Antiandrogens
Apoptosis
Binding sites
Cancer therapies
Cell cycle
Cell proliferation
Clinical trials
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Flow cytometry
Gene expression
Ionizing radiation
Ligands
Medical prognosis
Mutation
Prostate cancer
Proteins
Radiation therapy
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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.
AbstractList 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.
Author Leung, Jacky K
Banuelos, Carmen A
Sadar, Marianne D
Andersen, Raymond J
Obst, Jon K
Mawji, Nasrin R
Ito, Yusuke
Wang, Jun
Tien, Amy H
Hirayama, Yukiyoshi
Tam, Teresa
AuthorAffiliation 2 Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada; raymond.andersen@ubc.ca
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.)
3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada
AuthorAffiliation_xml – name: 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.)
– name: 3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada
– name: 2 Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada; raymond.andersen@ubc.ca
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Snippet Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high...
SourceID pubmedcentral
proquest
crossref
SourceType Open Access Repository
Aggregation Database
StartPage 1991
SubjectTerms Alternative splicing
Androgen receptors
Androgens
Antiandrogens
Apoptosis
Binding sites
Cancer therapies
Cell cycle
Cell proliferation
Clinical trials
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Flow cytometry
Gene expression
Ionizing radiation
Ligands
Medical prognosis
Mutation
Prostate cancer
Proteins
Radiation therapy
Transcription
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Title Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
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Volume 12
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