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Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()

BACKGROUND AND PURPOSE: In muscle-invasive bladder cancer there is an urgent need to identify relatively non-toxic radiosensitising agents for use in elderly patients. Histone deacetylase inhibitors radiosensitise tumour cells but not normal cells in vitro and variously downregulate DNA damage signa...

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Autores principales: Groselj, Blaz, Kerr, Martin, Kiltie, Anne E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Scientific Publishers 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824066/
https://www.ncbi.nlm.nih.gov/pubmed/23932191
http://dx.doi.org/10.1016/j.radonc.2013.06.021
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author Groselj, Blaz
Kerr, Martin
Kiltie, Anne E.
author_facet Groselj, Blaz
Kerr, Martin
Kiltie, Anne E.
author_sort Groselj, Blaz
collection PubMed
description BACKGROUND AND PURPOSE: In muscle-invasive bladder cancer there is an urgent need to identify relatively non-toxic radiosensitising agents for use in elderly patients. Histone deacetylase inhibitors radiosensitise tumour cells but not normal cells in vitro and variously downregulate DNA damage signalling, homologous recombination (HR) and non-homologous end-joining (NHEJ) repair proteins. We investigated panobinostat (PAN) as a potential radiosensitiser in bladder cancer cells. MATERIALS AND METHODS: Clonogenic assays were performed in RT112 bladder cancer cells, and RT112 cells stably knocked down for RAD51 or Ku80 by shRNAi. Resolution of γH2AX foci was determined by immunofluorescence confocal microscopy, cell cycle progression by FACS analysis and protein expression by western blotting. RESULTS: PAN had a greater radiosensitising effect in Ku80KD than RT112 or RAD51KD cells; enhancement ratios 1.35 for Ku80KD at 10 nM (IC(20) for Ku80KD) and 1.31 for RT112 and RAD51KD at 25 nM (IC(40) for both). PAN downregulated MRE11, NBS1 and RAD51, but not Ku70 and Ku80, increased γH2AX foci formation in a dose-dependent manner and delayed γH2AX foci repair after ionising radiation. CONCLUSIONS: PAN acts as a radiosensitiser in bladder cancer cell lines, and appears to target HR rather than NHEJ. As muscle-invasive bladder tumours have reduced Ku-DNA binding, PAN could be particularly useful as a radiosensitiser in bladder cancer.
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spelling pubmed-38240662013-11-12 Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression() Groselj, Blaz Kerr, Martin Kiltie, Anne E. Radiother Oncol Molecular Radiobiology BACKGROUND AND PURPOSE: In muscle-invasive bladder cancer there is an urgent need to identify relatively non-toxic radiosensitising agents for use in elderly patients. Histone deacetylase inhibitors radiosensitise tumour cells but not normal cells in vitro and variously downregulate DNA damage signalling, homologous recombination (HR) and non-homologous end-joining (NHEJ) repair proteins. We investigated panobinostat (PAN) as a potential radiosensitiser in bladder cancer cells. MATERIALS AND METHODS: Clonogenic assays were performed in RT112 bladder cancer cells, and RT112 cells stably knocked down for RAD51 or Ku80 by shRNAi. Resolution of γH2AX foci was determined by immunofluorescence confocal microscopy, cell cycle progression by FACS analysis and protein expression by western blotting. RESULTS: PAN had a greater radiosensitising effect in Ku80KD than RT112 or RAD51KD cells; enhancement ratios 1.35 for Ku80KD at 10 nM (IC(20) for Ku80KD) and 1.31 for RT112 and RAD51KD at 25 nM (IC(40) for both). PAN downregulated MRE11, NBS1 and RAD51, but not Ku70 and Ku80, increased γH2AX foci formation in a dose-dependent manner and delayed γH2AX foci repair after ionising radiation. CONCLUSIONS: PAN acts as a radiosensitiser in bladder cancer cell lines, and appears to target HR rather than NHEJ. As muscle-invasive bladder tumours have reduced Ku-DNA binding, PAN could be particularly useful as a radiosensitiser in bladder cancer. Elsevier Scientific Publishers 2013-09 /pmc/articles/PMC3824066/ /pubmed/23932191 http://dx.doi.org/10.1016/j.radonc.2013.06.021 Text en © 2013 The Authors https://creativecommons.org/licenses/by-nc-nd/3.0/ Open Access under CC BY-NC-ND 3.0 (https://creativecommons.org/licenses/by-nc-nd/3.0/) license
spellingShingle Molecular Radiobiology
Groselj, Blaz
Kerr, Martin
Kiltie, Anne E.
Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()
title Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()
title_full Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()
title_fullStr Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()
title_full_unstemmed Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()
title_short Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression()
title_sort radiosensitisation of bladder cancer cells by panobinostat is modulated by ku80 expression()
topic Molecular Radiobiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824066/
https://www.ncbi.nlm.nih.gov/pubmed/23932191
http://dx.doi.org/10.1016/j.radonc.2013.06.021
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