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VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation

BACKGROUND: High linear energy transfer (LET) radiation such as carbon ion particles is successfully used for treatment of solid tumors. The reason why high LET radiation accomplishes greater tumor-killing than X-rays is still not completely understood. One factor would be the clustered or complex-t...

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Autores principales: Fujisawa, Hiroshi, Nakajima, Nakako Izumi, Sunada, Shigeaki, Lee, Younghyun, Hirakawa, Hirokazu, Yajima, Hirohiko, Fujimori, Akira, Uesaka, Mitsuru, Okayasu, Ryuichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554350/
https://www.ncbi.nlm.nih.gov/pubmed/26286029
http://dx.doi.org/10.1186/s13014-015-0464-y
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author Fujisawa, Hiroshi
Nakajima, Nakako Izumi
Sunada, Shigeaki
Lee, Younghyun
Hirakawa, Hirokazu
Yajima, Hirohiko
Fujimori, Akira
Uesaka, Mitsuru
Okayasu, Ryuichi
author_facet Fujisawa, Hiroshi
Nakajima, Nakako Izumi
Sunada, Shigeaki
Lee, Younghyun
Hirakawa, Hirokazu
Yajima, Hirohiko
Fujimori, Akira
Uesaka, Mitsuru
Okayasu, Ryuichi
author_sort Fujisawa, Hiroshi
collection PubMed
description BACKGROUND: High linear energy transfer (LET) radiation such as carbon ion particles is successfully used for treatment of solid tumors. The reason why high LET radiation accomplishes greater tumor-killing than X-rays is still not completely understood. One factor would be the clustered or complex-type DNA damages. We previously reported that complex DNA double-strand breaks produced by high LET radiation enhanced DNA end resection, and this could lead to higher kinase activity of ATR protein recruited to RPA-coated single-stranded DNA. Although the effect of ATR inhibition on cells exposed to low LET gamma-rays has recently been reported, little is known regarding the effect of ATR inhibitor on cells treated with high LET radiation. The purpose of this study is to investigate the effects of the ATR inhibitor VE-821 in human tumor and normal cells irradiated with high LET carbon ions. FINDINGS: HeLa, U2OS, and 1BR-hTERT (normal) cells were pre-treated with 1 μM VE-821 for 1 hour and irradiated with either high LET carbon ions or X-rays. Cell survival, cell cycle distribution, cell growth, and micronuclei formation were evaluated. VE-821 caused abrogation of G2/M checkpoint and forced irradiated cells to divide into daughter cells. We also found that carbon ions caused a higher number of multiple micronuclei than X-rays, leading to decreased cell survival in tumor cells when treated with VE-821, while the survival of irradiated normal cells were not significantly affected by this inhibitor. CONCLUSIONS: ATR inhibitor would be an effective tumor radiosensitizer with carbon ion irradiation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-015-0464-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-45543502015-09-01 VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation Fujisawa, Hiroshi Nakajima, Nakako Izumi Sunada, Shigeaki Lee, Younghyun Hirakawa, Hirokazu Yajima, Hirohiko Fujimori, Akira Uesaka, Mitsuru Okayasu, Ryuichi Radiat Oncol Short Report BACKGROUND: High linear energy transfer (LET) radiation such as carbon ion particles is successfully used for treatment of solid tumors. The reason why high LET radiation accomplishes greater tumor-killing than X-rays is still not completely understood. One factor would be the clustered or complex-type DNA damages. We previously reported that complex DNA double-strand breaks produced by high LET radiation enhanced DNA end resection, and this could lead to higher kinase activity of ATR protein recruited to RPA-coated single-stranded DNA. Although the effect of ATR inhibition on cells exposed to low LET gamma-rays has recently been reported, little is known regarding the effect of ATR inhibitor on cells treated with high LET radiation. The purpose of this study is to investigate the effects of the ATR inhibitor VE-821 in human tumor and normal cells irradiated with high LET carbon ions. FINDINGS: HeLa, U2OS, and 1BR-hTERT (normal) cells were pre-treated with 1 μM VE-821 for 1 hour and irradiated with either high LET carbon ions or X-rays. Cell survival, cell cycle distribution, cell growth, and micronuclei formation were evaluated. VE-821 caused abrogation of G2/M checkpoint and forced irradiated cells to divide into daughter cells. We also found that carbon ions caused a higher number of multiple micronuclei than X-rays, leading to decreased cell survival in tumor cells when treated with VE-821, while the survival of irradiated normal cells were not significantly affected by this inhibitor. CONCLUSIONS: ATR inhibitor would be an effective tumor radiosensitizer with carbon ion irradiation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-015-0464-y) contains supplementary material, which is available to authorized users. BioMed Central 2015-08-19 /pmc/articles/PMC4554350/ /pubmed/26286029 http://dx.doi.org/10.1186/s13014-015-0464-y Text en © Fujisawa et.al. 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Short Report
Fujisawa, Hiroshi
Nakajima, Nakako Izumi
Sunada, Shigeaki
Lee, Younghyun
Hirakawa, Hirokazu
Yajima, Hirohiko
Fujimori, Akira
Uesaka, Mitsuru
Okayasu, Ryuichi
VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
title VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
title_full VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
title_fullStr VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
title_full_unstemmed VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
title_short VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation
title_sort ve-821, an atr inhibitor, causes radiosensitization in human tumor cells irradiated with high let radiation
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554350/
https://www.ncbi.nlm.nih.gov/pubmed/26286029
http://dx.doi.org/10.1186/s13014-015-0464-y
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