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-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.


RESULTS
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.
Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8656, Japan. fujisawa@nuclear.jp.|Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. fujisawa@nuclear.jp.
Hiroshi
H
Fujisawa
Research Center for Charged Particle Therapy/International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. nakako@nirs.go.jp.
Nakako Izumi
NI
Nakajima
Department of Nuclear Engineering and Management, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8656, Japan. sunada@nuclear.jp.|Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. sunada@nuclear.jp.
Shigeaki
S
Sunada
Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. ylee@nirs.go.jp.
Younghyun
Y
Lee
Research Center for Charged Particle Therapy/International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. hirakawa@nirs.go.jp.|Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. hirakawa@nirs.go.jp.
Hirokazu
H
Hirakawa
Research Center for Charged Particle Therapy/International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. hyajima@nirs.go.jp.
Hirohiko
H
Yajima
Research Center for Charged Particle Therapy/International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. fujimora@nirs.go.jp.|Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. fujimora@nirs.go.jp.
Akira
A
Fujimori
Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8656, Japan. uesaka@nuclear.jp.|Department of Nuclear Engineering and Management, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8656, Japan. uesaka@nuclear.jp.
Mitsuru
M
Uesaka
Research Center for Charged Particle Therapy/International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. rokayasu@nirs.go.jp.|Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan. rokayasu@nirs.go.jp.
Ryuichi
R
Okayasu
D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D063193:Heavy Ion Radiotherapy; D006801:Humans; D018499:Linear Energy Transfer; D011719:Pyrazines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
C560580:3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D013450:Sulfones; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins