Medical Radiology and Radiation Safety. 2025. Vol. 70. № 4
DOI:10.33266/1024-6177-2025-70-4-10-15
D.V. Molodtsova1, 2, E.A. Kotenkova3, E.K. Polishchuk4, A.A. Osipov2,
D.V. Guryev1, A.K. Chigasova1, 2, 5, N.Yu. Vorobyeva1, 2, A.N. Osipov1, 2, 3
Sensitivity to Chemoradiation Effects of Human Non-Small Cell Lung Cancer Cells Surviving Fractionated Irradiation with a Total Dose of 20 Gy
1 A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
2 N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia
3 Moscow Institute of Physics and Technology (National Research University), Moscow Region, Dolgoprudny, Russia
4 Experimental clinic and research laboratory for bioactive substances of animal origin, V.M. Gorbatov Federal Research Center for Food Systems, Moscow, Russia
5 N.M. Emanuel Institute for Biochemical Physics, Moscow, Russia
Contact person: D.V. Molodtsova, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
Objective: To obtain human non-small cell lung cancer (NSCLC) cells that survived and showed stable growth after fractionated exposure to X-rays at a total dose of 20 Gy and to evaluate their sensitivity to additional irradiation and cisplatin.
Material and methods: The NSCLC cell line A549 was used in the study, and it was irradiated in the fractionated mode (5 fractions of 4 Gy) to obtain a subline of surviving cells – A549IR. A549 and A549IR cells were subjected to testing exposure to X-rays or cisplatin. Then, proliferative activity, 2D migration capacity and the efficiency of DNA double-strand break (DSB) repair were analyzed using a quantitative assessment of residual foci of the γH2AX and 53BP1 proteins.
Results: The study yielded NSCLC cells that survived and showed stable growth after fractionated X-ray irradiation with a total dose of 20 Gy. The resulting A549IR cells had altered morphology, decreased proliferative activity, and increased migration capacity. Analysis of residual 53BP1 foci after test irradiation with a dose of 6 Gy indicates increased efficiency of repair of radiation-induced DNA DSBs. It was also found that A549IR cells are more resistant to cisplatin.
Conclusion: Overall, the study results show that combination CRT for the treatment of NSCLC should be prescribed with caution if studies based on the animal model support current conclusions. NSCLC cells that have survived IR exposure may acquire resistance to cisplatin. To select the appropriate therapy, it is important to assess both the existing radio- and chemo-resistance of tumor cells and their resistance to therapeutic effects that developed during treatment.
Keywords: NSCLC cells, Х-ray irradiation, сisplatin, γH2AX, 53BP1, residual foci, DNA double-strand breaks
For citation: Molodtsova DV, Kotenkova EA, Polishchuk EK, Osipov AA, Guryev DV, Chigasova AK, Vorobyeva NYu, Osipov AN. Sensitivity to Chemoradiation Effects of Human Non-Small Cell Lung Cancer Cells Surviving Fractionated Irradiation with a Total Dose of 20 Gy. Medical Radiology and Radiation Safety. 2025;70(4):10–15. (In Russian). DOI:10.33266/1024-6177-2025-70-4-10-15
References
1. Watanabe S-i., Nakagawa K., Suzuki K., Takamochi K., Ito H., Okami J., et al. Neoadjuvant and Adjuvant Therapy for Stage III Non-Small Cell Lung Cancer. Japanese Journal of Clinical Oncology. 2017;47;12:1112-8. doi: 10.1093/jjco/hyx147.
2. Hao W., Wu L., Cao L., Yu J., Ning L., Wang J., et al. Radioresistant Nasopharyngeal Carcinoma Cells Exhibited Decreased Cisplatin Sensitivity by Inducing SLC1A6 Expression. Frontiers in Pharmacology. 2021;12:629264. doi: 10.3389/fphar.2021.629264.
3. Gomez-Casal R., Epperly M.W., Wang H., Proia D.A., Greenberger J.S., Levina V. Radioresistant Human Lung Adenocarcinoma Cells that Survived Multiple Fractions of Ionizing Radiation are Sensitive to HSP90 Inhibition. Oncotarget. 2015;6;42:44306-22. doi: 10.18632/oncotarget.6248.
4. Wang Y., Huang J., Wu Q., Zhang J., Ma Z., Ma S., et al. Downregulation of Breast Cancer Resistance Protein by Long-Term Fractionated Radiotherapy Sensitizes Lung Adenocarcinoma to SN-38. Investigational New Drugs. 2021;39;2:458-68. doi: 10.1007/s10637-020-01003-3.
5. Payton C., Pang L.Y., Gray M., Argyle D.J. Exosomes Derived from Radioresistant Breast Cancer Cells Promote Therapeutic Resistance in Naïve Recipient Cells. Journal of Personalized Medicine. 2021;11;12. doi: 10.3390/jpm11121310.
6. Wang Y., Huang J., Wu Q., Zhang J., Ma Z., Zhu L., et al. Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha. Frontiers in Oncology. 2021;11:668798. doi: 10.3389/fonc.2021.668798.
7. Alhaddad L., Osipov A.N., Leonov S. The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance. International Journal of Molecular Sciences. 2022;23;21:13577 doi: 10.3390/ijms232113577.
8. Molodtsova D., Guryev D.V., Osipov A.N. Composition of Conditioned Media from Radioresistant and Chemoresistant Cancer Cells Reveals miRNA and other Secretory Factors Implicated in the Development of Resistance. International Journal of Molecular Sciences. 2023;24;22:16498. doi: 10.3390/ijms242216498.
9. Babayan N., Grigoryan B., Khondkaryan L., Tadevosyan G., Sarkisyan N., Grigoryan R., et al. Laser-Driven Ultrashort Pulsed Electron Beam Radiation at Doses of 0.5 and 1.0 Gy Induces Apoptosis in Human Fibroblasts. International Journal of Molecular Sciences. 2019;20;20:51-40 doi: 10.3390/ijms20205140.
10. Shibata A., Jeggo P.A. Roles for 53BP1 in the Repair of Radiation-Induced DNA Double Strand Breaks. DNA Repair. 2020;93:102915. doi: 10.1016/j.dnarep.2020.102915.
11. Osipov A.N., Pustovalova M., Grekhova A., Eremin P., Vorobyova N., Pulin A., et al. Low Doses of X-Rays Induce Prolonged and ATM-Independent Persistence of γH2AX Foci in Human Gingival Mesenchymal Stem Cells. Oncotarget. 2015;6;29:27275-87. doi: 10.18632/oncotarget.4739.
12. Osipov A., Chigasova A., Yashkina E., Ignatov M., Vorobyeva N., Zyuzikov N., et al. Early and Late Effects of Low-Dose X-ray Exposure in Human Fibroblasts: DNA Repair Foci, Proliferation, Autophagy, and Senescence. International Journal of Molecular Sciences. 2024;25;15:8253 doi: 10.3390/ijms25158253.
13. Chigasova A.K., Pustovalova M.V., Osipov A.A., Korneva S.A., Eremin P.S., Yashkina E.I., et al. Post-Radiation Changes in The Number of Phosphorylated H2ax and Atm Protein Foci in Low Dose X-Ray Irradiated Human Mesenchymal Stem Cells. Medical Radiology and Radiation Safety. 2024;69;1:15-9. doi: 10.33266/1024-6177-2024-69-1-15-19.
14. Osipov A., Chigasova A., Belov O., Yashkina E., Ignatov M., Fedotov Y., et al. Dose Threshold for Residual γH2AX, 53BP1, pATM and p-p53 (Ser-15) Foci in X-Ray Irradiated Human Fibroblasts. International Journal of Radiation Biology. 2025;101;3:1-10. doi: 10.1080/09553002.2024.2445581.
15. Osipov A., Chigasova A., Yashkina E., Ignatov M., Fedotov Y., Molodtsova D., et al. Residual Foci of DNA Damage Response Proteins in Relation to Cellular Senescence and Autophagy in X-Ray Irradiated Fibroblasts. Cells. 2023;12;8:1209 doi: 10.3390/cells12081209.
16. Djuzenova C.S., Zimmermann M., Katzer A., Fiedler V., Distel L.V., Gasser M., et al. A Prospective Study on Histone γ-H2AX and 53BP1 Foci Expression in Rectal Carcinoma Patients: Correlation with Radiation Therapy-Induced Outcome. BMC Cancer. 2015;15;1:856. doi: 10.1186/s12885-015-1890-9.
17. Katsube T., Mori M., Tsuji H., Shiomi T., Wang B., Liu Q., et al. Most Hydrogen Peroxide-Induced Histone H2AX Phosphorylation is Mediated by ATR and is not Dependent on DNA Double-Strand Breaks. Journal of Biochemistry. 2014;156;2:85-95. doi: 10.1093/jb/mvu021.
18. Arcangeli S., Greco C. Hypofractionated Radiotherapy for Organ-Confined Prostate Cancer: is Less More? Nature Reviews Urology. 2016;13;7:400-8. doi: 10.1038/nrurol.2016.106.
PDF (RUS) Full-text article (in Russian)
Conflict of interest. The authors declare no conflict of interest.
Financing. The research was carried out with the support of the State Research Assignment cipher «Signal» (registration number in the EGISU R&D system: 123011200048-4).
Contribution. Writing: D.V. Molodtsova, A.N. Osipov; Experimental planning: D.V. Molodtsova, N.Yu. Vorobyeva, A.N. Osipov, D.V. Guryev; Experimental work: D.V. Molodtsova, N.Yu. Vorobyeva, E.A. Kotenkova, E.K. Polishchuk, A.A. Osipov, A.K. Chigasova; Vizualization: A.N. Osipov.
Article received: 20.03.2025. Accepted for publication: 25.04.2025.