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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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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409302/
https://www.ncbi.nlm.nih.gov/pubmed/32708219
http://dx.doi.org/10.3390/cancers12071991
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author 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.
author_facet 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.
author_sort Banuelos, Carmen A.
collection PubMed
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.
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spelling pubmed-74093022020-08-25 Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants 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. Cancers (Basel) Article 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. MDPI 2020-07-21 /pmc/articles/PMC7409302/ /pubmed/32708219 http://dx.doi.org/10.3390/cancers12071991 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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.
Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
title Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
title_full Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
title_fullStr Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
title_full_unstemmed Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
title_short Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
title_sort ralaniten sensitizes enzalutamide-resistant prostate cancer to ionizing radiation in prostate cancer cells that express androgen receptor splice variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409302/
https://www.ncbi.nlm.nih.gov/pubmed/32708219
http://dx.doi.org/10.3390/cancers12071991
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