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

Radiation Oncology

Ryuichi Okayasu¹  Mitsuru Uesaka²  Akira Fujimori¹  Hirohiko Yajima³  Hirokazu Hirakawa¹  Younghyun Lee¹  Shigeaki Sunada¹  Nakako Izumi Nakajima³  Hiroshi Fujisawa¹ 

[1]Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage 263-8555, Chiba, Japan

[2]Department of Nuclear Engineering and Management, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo 113-8656, Tokyo, Japan

[3]Research Center for Charged Particle Therapy/International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage 263-8555, Chiba, Japan

关键词: VE-821;    High LET radiation;    Cell cycle checkpoint;    Carbon ions;    ATR inhibition;   

Others  :  1228470
DOI  :  10.1186/s13014-015-0464-y

 received in 2015-05-13, accepted in 2015-07-15,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Fujisawa et.al.

【 图 表 】

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【 参考文献 】

• [1]Durante M, Loeffler JS. Charged particles in radiation oncology. Nat Rev Clin Oncol. 2010; 7(1):37-43.
• [2]Marx V. Cancer treatment: Sharp shooters. Nature. 2014; 508(7494):133-8.
• [3]Okayasu R. Repair of DNA damage induced by accelerated heavy ions--a mini review. Int J Cancer. 2012; 130(5):991-1000.
• [4]Yajima H, Fujisawa H, Nakajima NI, Hirakawa H, Jeggo PA, Okayasu R et al.. The complexity of DNA double strand breaks is a critical factor enhancing end-resection. DNA Repair (Amst). 2013; 12(11):936-46.
• [5]Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A et al.. Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J. 2011; 30(6):1079-92.
• [6]Asaithamby A, Hu B, Chen DJ. Unrepaired clustered DNA lesions induce chromosome breakage in human cells. Proc Natl Acad Sci U S A. 2011; 108(20):8293-8.
• [7]Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003; 300(5625):1542-8.
• [8]Flynn RL, Zou L. ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci. 2011; 36(3):133-40.
• [9]Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG et al.. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012; 13(11):1072-81.
• [10]Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA et al.. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011; 7(7):428-30.
• [11]Vavrova J, Zarybnicka L, Lukasova E, Rezacova M, Novotna E, Sinkorova Z et al.. Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60). Radiat Environ Biophys. 2013; 52(4):471-9.
• [12]Xue L, Furusawa Y, Okayasu R, Miura M, Cui X, Liu C et al.. The complexity of DNA double strand break is a crucial factor for activating ATR signaling pathway for G2/M checkpoint regulation regardless of ATM function. DNA Repair (Amst). 2015; 25:72-83.
• [13]Mantovani F, Banks L. The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene. 2001; 20(54):7874-87.
• [14]Pires IM, Olcina MM, Anbalagan S, Pollard JR, Reaper PM, Charlton PA et al.. Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br J Cancer. 2012; 107(2):291-9.