Predictive DNA damage signaling for low‑dose ionizing radiation Corrigendum in /10.3892/ijmm.2025.5553

Park,Jeong-In; Jung,Seung-Youn; Song,Kyung-Hee; Lee,Dong-Hyeon; Ahn,Jiyeon; Hwang,Sang-Gu; Jung,In-Su; Lim,Dae-Seog; Song,Jie-Young

doi:10.3892/ijmm.2024.5380

June-2024 Volume 53 Issue 6

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

June-2024 Volume 53 Issue 6

Full Size Image

Article Open Access

Predictive DNA damage signaling for low‑dose ionizing radiation

Corrigendum in: /10.3892/ijmm.2025.5553

Authors:
- Jeong-In Park
- Seung-Youn Jung
- Kyung-Hee Song
- Dong-Hyeon Lee
- Jiyeon Ahn
- Sang-Gu Hwang
- In-Su Jung
- Dae-Seog Lim
- Jie-Young Song
View Affiliations / Copyright

Affiliations: Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea, Department of Biotechnology, CHA University, Seongnam, Gyeonggi‑do 13488, Republic of Korea

Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 56
|
Published online on: April 30, 2024

https://doi.org/10.3892/ijmm.2024.5380
Expand metrics +

Abstract

Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for low‑dose radiation‑sensitive markers. The HuT 78 and IM‑9 cell lines were irradiated in a concentration‑dependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentration‑dependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sub‑lethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sub‑lethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML‑277, pifithrin‑α, and nutlin‑3a were evaluated for their ability to modulate radiation‑induced cell death. The use of BML‑277 led to a decrease in radiation‑induced p‑CHK2 and γH2AX levels and mitigated radiation‑induced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiation‑sensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.

View Figures

View References

1	Moding EJ, Kastan MB and Kirsch DG: Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov. 12:526–542. 2013. View Article : Google Scholar : PubMed/NCBI
2	Wang JS, Wang HJ and Qian HL: Biological effects of radiation on cancer cells. Mil Med Res. 5:202018.PubMed/NCBI
3	Wang H, Mu X, He H and Zhang XD: Cancer radiosensitizers. Trends Pharmacol Sci. 39:24–48. 2018. View Article : Google Scholar
4	Sokolov M and Neumann R: Effects of low doses of ionizing radiation exposures on stress-responsive gene expression in human embryonic stem cells. Int J Mol Sci. 15:588–604. 2014. View Article : Google Scholar : PubMed/NCBI
5	Nowsheen S and Yang ES: The intersection between DNA damage response and cell death pathways. Exp Oncol. 34:243–254. 2012.PubMed/NCBI
6	Xu J, Liu D, Zhao D, Jiang X, Meng X, Jiang L, Yu M, Zhang L and Jiang H: Role of low-dose radiation in senescence and aging: A beneficial perspective. Life Sci. 302:1206442022. View Article : Google Scholar : PubMed/NCBI
7	Ossetrova NI and Blakely WF: Multiple blood-proteins approach for early-response exposure assessment using an in vivo murine radiation model. Int J Radiat Biol. 85:837–850. 2009.PubMed/NCBI
8	Zhang M, Yin L, Zhang K, Sun W, Yang S, Zhang B, Salzman P, Wang W, Liu C, Vidyasagar S, et al: Response patterns of cytokines/chemokines in two murine strains after irradiation. Cytokine. 58:169–177. 2012. View Article : Google Scholar : PubMed/NCBI
9	Mathias D, Mitchel RE, Barclay M, Wyatt H, Bugden M, Priest ND, Whitman SC, Scholz M, Hildebrandt G, Kamprad M and Glasow A: Low-dose irradiation affects expression of inflammatory markers in the heart of ApoE -/- mice. PLoS One. 10:e01196612015. View Article : Google Scholar : PubMed/NCBI
10	Marchetti F, Coleman MA, Jones IM and Wyrobek AJ: Candidate protein biodosimeters of human exposure to ionizing radiation. Int J Radiat Biol. 82:605–639. 2006. View Article : Google Scholar : PubMed/NCBI
11	Gu J, Chen YZ, Zhang ZX, Yang ZX, Duan GX, Qin LQ, Zhao L and Xu JY: At what dose can total body and whole abdominal irradiation cause lethal intestinal injury among C57BL/6J mice? Dose Response. 18:15593258209567832020. View Article : Google Scholar : PubMed/NCBI
12	Pan Z, Zhang X, Yu P, Chen X, Lu P, Li M, Liu X, Li Z, Wei F, Wang K, et al: Cinobufagin induces cell cycle arrest at the G2/M phase and promotes apoptosis in malignant melanoma cells. Front Oncol. 9:8532019. View Article : Google Scholar : PubMed/NCBI
13	Grahn D and Hamilton KF: Genetic variation in the acute lethal response of four inbred mouse strains to whole body X-irradiation. Genetics. 42:189–198. 1957. View Article : Google Scholar : PubMed/NCBI
14	Soto-Pantoja DR, Ridnour LA, Wink DA and Roberts DD: Blockade of CD47 increases survival of mice exposed to lethal total body irradiation. Sci Rep. 3:10382013. View Article : Google Scholar : PubMed/NCBI
15	Li L, Xiao R, Wang Q, Rong Z, Zhang X, Zhou P, Fu H, Wang S and Wang Z: SERS detection of radiation injury biomarkers in mouse serum. RSC Adv. 8:5119–5126. 2018. View Article : Google Scholar : PubMed/NCBI
16	Ito Y, Kinoshita M, Yamamoto T, Sato T, Obara T, Saitoh D, Seki S and Takahashi Y: A combination of pre- and post-exposure ascorbic acid rescues mice from radiation-induced lethal gastrointestinal damage. Int J Mol Sci. 14:19618–19635. 2013. View Article : Google Scholar : PubMed/NCBI
17	Nunamaker EA, Artwohl JE, Anderson RJ and Fortman JD: Endpoint refinement for total body irradiation of C57BL/6 mice. Comp Med. 63:22–28. 2013.PubMed/NCBI
18	Mettler FA: Medical effects and risks of exposure to ionising radiation. J Radiol Prot. 32:N9–N13. 2012. View Article : Google Scholar : PubMed/NCBI
19	Seo S, Lee D, Seong KM, Park S, Kim SG, Won JU and Jin YW: Radiation-related occupational cancer and its recognition criteria in South Korea. Ann Occup Environ Med. 30:92018. View Article : Google Scholar : PubMed/NCBI
20	Allan JM and Travis LB: Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer. 5:943–955. 2005. View Article : Google Scholar : PubMed/NCBI
21	Little JB: Radiation carcinogenesis. Carcinogenesis. 21:397–404. 2000. View Article : Google Scholar : PubMed/NCBI
22	Barcellos-Hoff MH and Nguyen DH: Radiation carcinogenesis in context: How do irradiated tissues become tumors? Health Phys. 97:446–457. 2009. View Article : Google Scholar : PubMed/NCBI
23	Huang L, Snyder AR and Morgan WF: Radiation-induced genomic instability and its implications for radiation carcinogenesis. Oncogene. 22:5848–5854. 2003. View Article : Google Scholar : PubMed/NCBI
24	Obrador E, Salvador-Palmer R, Villaescusa JI, Gallego E, Pellicer B, Estrela JM and Montoro A: Nuclear and radiological emergencies: biological effects, countermeasures and biodosimetry. Antioxidants (Basel). 11:10892022.
25	Turtoi A, Brown I, Oskamp D and Schneeweiss FHA: Early gene expression in human lymphocytes after gamma-irradiation-a genetic pattern with potential for biodosimetry. Int J Radiat Biol. 84:375–387. 2008. View Article : Google Scholar : PubMed/NCBI
26	Brengues M, Paap B, Bittner M, Amundson S, Seligmann B, Korn R, Lenigk R and Zenhausern F: Biodosimetry on small blood volume using gene expression assay. Health Phys. 98:179–185. 2010. View Article : Google Scholar : PubMed/NCBI
27	Dainiak N: Hematologic consequences of exposure to ionizing radiation. Exp Hematol. 30:513–528. 2002. View Article : Google Scholar : PubMed/NCBI
28	Shiloh Y and Ziv Y: The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 14:197–210. 2013. View Article : Google Scholar : PubMed/NCBI
29	Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Löbrich M and Jeggo PA: ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell. 31:167–177. 2008. View Article : Google Scholar : PubMed/NCBI
30	Helleday T, Petermann E, Lundin C, Hodgson B and Sharma RA: DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 8:193–204. 2008. View Article : Google Scholar : PubMed/NCBI
31	Jackson SP and Bartek J: The DNA-damage response in human biology and disease. Nature. 461:1071–1078. 2009. View Article : Google Scholar : PubMed/NCBI
32	Niu J, Wang J, Zhang Q, Zou Z and Ding Y: Cinobufagin-induced DNA damage response activates G₂/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells. Cancer Cell Int. 21:4462021. View Article : Google Scholar
33	Li Y, Lin J, Xiao J, Li Z, Chen JS, Wei L and Wang X: Therapeutic effects of co-Venenum bufonis oral liquid on radiation-induced esophagitis in rats. Exp Anim. 69:354–362. 2020. View Article : Google Scholar : PubMed/NCBI
34	Xie S, Spelmink L, Codemo M, Subramanian K, Pütsep K, Henriques-Normark B and Olliver M: Cinobufagin modulates human innate immune responses and triggers antibacterial activity. PLoS One. 11:e01607342016. View Article : Google Scholar : PubMed/NCBI
35	Peng P, Lv J, Cai C, Lin S, Zhuo E and Wang S: Cinobufagin, a bufadienolide, activates ROS-mediated pathways to trigger human lung cancer cell apoptosis in vivo. RSC Adv. 7:25175–25181. 2017. View Article : Google Scholar
36	Niu T, Zhao L, Lin X, Cai Y, Chen S, Wang M, Zhou L, Ding H and Yu X: Cinobufagin, a bufadienolide from traditional Chinese medicine Bufo bufo gargarizans CANTOR, inhibits PC3 cell growth in vitro and in vivo. J Tradit Chin Med Sci. 6:175–183. 2019.
37	Wu SC, Yi PF, Guo X, Zhang LY, Xu DX, Fu YX, Cui ZQ, Shen HQ, Wei XB and Fu BD: Cinobufagin enhances the protective efficacy of formalin-inactivated Salmonella typhimurium vaccine through Th1 immune response. Microb Pathog. 99:264–270. 2016. View Article : Google Scholar : PubMed/NCBI
38	Yu Y, Wang H, Meng X, Hao L, Fu Y, Fang L, Shen D, Yu X and Li J: Immunomodulatory effects of cinobufagin on murine lymphocytes and macrophages. Evid Based Complement Alternat Med. 2015:8352632015. View Article : Google Scholar : PubMed/NCBI
39	Matsuoka S, Huang M and Elledge SJ: Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 282:1893–1897. 1998. View Article : Google Scholar : PubMed/NCBI
40	Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ and Mak TW: DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science. 287:1824–1827. 2000. View Article : Google Scholar : PubMed/NCBI
41	Melchionna R, Chen XB, Blasina A and McGowan CH: Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1. Nat Cell Biol. 2:762–765. 2000. View Article : Google Scholar : PubMed/NCBI
42	Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K and Linn S: Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 73:39–85. 2004. View Article : Google Scholar : PubMed/NCBI
43	Rainey MD, Black EJ, Zachos G and Gillespie DAF: Chk2 is required for optimal mitotic delay in response to irradiation-induced DNA damage incurred in G2 phase. Oncogene. 27:896–906. 2008. View Article : Google Scholar
44	Nguyen TNT, Saleem RSZ, Luderer MJ, Hovde S, Henry RW and Tepe JJ: Radioprotection by hymenialdisine-derived checkpoint kinase 2 inhibitors. ACS Chem Biol. 7:172–184. 2012. View Article : Google Scholar
45	Zahmatkesh MH, Hosseinimehr SJ and Mahdiuni H: Role of CHK2 inhibitors in the cellular responses to ionizing radiation. Mini Rev Med Chem. 14:812–818. 2014. View Article : Google Scholar : PubMed/NCBI
46	Arienti KL, Brunmark A, Axe FU, McClure K, Lee A, Blevitt J, Neff DK, Huang L, Crawford S, Pandit CR, et al: Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles. J Med Chem. 48:1873–1885. 2005. View Article : Google Scholar : PubMed/NCBI
47	Takai H, Naka K, Okada Y, Watanabe M, Harada N, Saito S, Anderson CW, Appella E, Nakanishi M, Suzuki H, et al: Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21:5195–5205. 2002. View Article : Google Scholar : PubMed/NCBI
48	Jung SY, Park JI, Jeong JH, Song KH, Ahn J, Hwang SG, Kim J, Park JK, Lim DS and Song JY: Receptor interacting protein 1 knockdown induces cell death in liver cancer by suppressing STAT3/ATR activation in a p53-dependent manner. Am J Cancer Res. 12:2594–2611. 2022.PubMed/NCBI
49	Joerger AC and Fersht AR: The p53 pathway: Origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem. 85:375–404. 2016. View Article : Google Scholar : PubMed/NCBI