Issues journals
Medical Radiology and Radiation Safety. 2026. Vol. 71. № 5
DOI:10.33266/1024-6177-2026-71-5-7-12
Yu.D. Udalov, E.V. Goloborodko, A.S. Kretov
PERCEPTION OF IONIZING RADIATION: HISTORICAL REVIEW AND CURRENT UNDERSTANDINGS
A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
Contact person: E.V. Goloborodko, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
Introduction.
Results and Discussion:
1. Historical Research on the Radiophosphene Phenomenon (1896–1963):
1.1. First Observations of Light Sensation during Ocular Irradiation.
1.2. Electrophysiological Studies of the Retina.
1.3. Mechanisms of Radiophosphene: A Discussion of the Role of Fluorescence.
2. Behavioral Responses of Animals to Ionizing Radiation.
3. Conditioned Reflexes to Ionizing Radiation.
4. Human Perception of Radiation: Clinical Observations.
5. Current Research.
Conclusion.
Keywords: ionizing radiation, radiophosphane, radiomodulation, sensory perception, TRP channels, reactive oxygen species, conditioned reflexes, radiation therapy
For citation: Udalov YuD, Goloborodko EV, Kretov AS. Perception of Ionizing Radiation: Historical Review and Current Understandings. Medical Radiology and Radiation Safety. 2026;71(5):7–12. DOI:10.33266/1024-6177-2026-71-5-7-12
References
1. Ushakov I.B., Fedorov V.P. Malyye Radiatsionnyye Vozdeystviya i Mozg = Minor Radiation Exposures and the Brain. Voronezh, Nauchnaya Kniga Publ., 2015. 532 p. (In Russ.).
2. Yarmonenko S.P., Vaynson A.A. Radiobiologiya Cheloveka i Zhivotnykh = Radiobiology of Humans and Animals. A Textbook for Students of Medical and Biological Specialties at Universities. Moscow, Vysshaya Shkola Publ., 2004. 548 p. (In Russ.).
3. Tsypin A.B., Grigor’yev Yu.G. Quantitative Characteristics of CNS Sensitivity to Ionizing Radiation. Byulleten’ Eksperimental’noy Biologii i Meditsiny = Bulletin of Experimental Biology and Medicine. 1960;1:26-31 (In Russ.).
4. Livanov M.N., Biryukov D.A. Changes Arising in the Nervous System after Exposure to Ionizing Radiation. Radiobiologiya i Radiatsionnaya Meditsina = Radiobiology and Radiation Medicine. Proceedings of the Second International Conference on the Peaceful Uses of Atomic Energy. Moscow, Atomizdat, 1959. P. 69-80 (In Russ.).
5. Lebedinskiy A.V., Nakhil’nitskaya Z.N. Vliyaniye Ioniziruyushchikh Izlucheniy na Nervnuyu Sistemu = The Effect of Ionizing Radiation on the Nervous System. Moscow, Atomizdat Publ., 1960. 187 p. (In Russ.).
6. Bergon’ye ZH., Tribondo L. Interpretation of Some Results of Radiotherapy and an Attempt to Determine a Rational Treatment Technique. Novaya Meditsina Tysyacheletiya = New Medicine of the Millennium. 2010;3:10-11 (In Russ.).
7. Rowe C., Santiago N., Warner J., Tsytsarev V., Rozhkova E.A., Ngwu-Hyacinth O., Bolding M. Human Perception of Ionizing Radiation. Physics of Life Reviews. 2025;53:1–21.
8. Tsypin A.B. Ioniziruyushchaya Radiatsiya kak Razdrazhitel’ Nervnoy Sistemy = Ionizing Radiation as an Irritant of the Nervous System. Extended Abstract of Doctor’s Thesis (Med.). Moscow, Akademiya Meditsinskikh Nauk SSSR Publ., 1964. 23 p. (In Russ.).
9. London Ye.S. O Fiziologicheskom Znachenii Radiya = On the physiological significance of radium. St. Petersburg, Tipografiya M.M. Stasyulevicha Publ., 1903. 15 p. (In Russ.).
10. Himstedt F., Nagel W.A. Ueber die Einwirkung der Becquerel‐und der Röntgenstrahlen auf das Auge. Annalen der Physik. 1901;309;3:537-52.
11. Lipetz L.E. The X-Ray and Radium Phosphenes. Br J Ophthalmol. 1955;39;10:577-98.
12. Lipetz L.E. Electrophysiology of the X-Ray Phosphene. Radiat Res. 1955;2;4:306-29.
13. Newell R.R., Barley W.E. Roentgen Measurement of Visual Acuity in Cataractous Eyes. Radiology. 1941;37;1:54-61.
14. Overall J.E., Logie L.C., Brown W.L. Changes in the Shuttle-Box Behavior in Albino Rats in Response to X-Irradiation at 1 R/ min. Radiat Res. 1959;11:589-99.
15. Andrews H.L., Cameron L.M. Radiation Avoidance in the Mouse. Proc Soc Exp Biol Med. 1960 Mar;103:565-7.
16. Hunt E.L., Kimeldorf D.J. Behavioral Arousal and Neural Activation as Radiosensitive Reactions. Radiat Res. 1964 Jan;21:91-110.
17. Khrushchev V.G., Darenskaya N.G., Pravdina G.M. Behavior of Mice in a Gamma-Radiation Field. Radiobiologiya = Radiobiology. 1961;6;1:940-945 (In Russ.).
18. Khrushchev V.G., Pravdina G.M., Darenskaya N.G. Behavior of the Fruit Fly (Drosophila Melanogaster) during Radiation Exposure. Radiobiologiya = Radiobiology. 1962;2;2:272-277 (In Russ.).
19. Movsesyan M.A., Grigoryan G.T., Avakimova E.A. On the Neuroreflex Mechanism of X-Ray Action. Izvestiya AN SSSR = Bulletin of the USSR Academy of Sciences. Biological and Agricultural Sciences. 1952;3:45-52 (In Russ.).
20. Livshits N.N. O Vozmozhnosti Vrednogo Vozdeystviya Ioniziruyushchikh Izlucheniy v Malykh Dozakh na Funktsii Zreloy Tsentral’noy Nervnoy Sistemy = On the Possibility of Harmful Effects of Ionizing Radiation in Small Doses on the Functions of the Mature Central Nervous System. Moscow, Atomizdat Publ., 1968. 10 p. (In Russ.).
21. Livshits N.N., Meyzerov Ye.S. The Effect of Long-Acting Conditioned Stimuli, Previously Combined with X-Ray Irradiation, on the Content of Leukocytes and Lymphocytes in Peripheral Blood. Radiobiologiya = Radiobiology. 1961;1;2:223-229 (In Russ.).
22. Garcia J., Kimeldorf D.J., Hunt E.L., Davies B.P. Food and Water Consumption of Rats during Exposure to Gamma-Radiation. Radiat Res. 1956;4;1:33-41.
23. Garcia J., Kimeldorf D.J., Hunt E.L. Spatial Avoidance in the Rat as a Result of Exposure to Ionizing Radiation. Br J Radiol. 1957;30;354:318-321.
24. Garcia J., Kimeldorf D.J., Koelling R.A. Conditioned Aversion to Saccharin Resulting from Exposure to Gamma Radiation. Science. 1955;122;3160:157-158.
25. Garcia J., Kimeldorf D.J. Some Factors which Influence Radiation-Conditioned Behavior of Rats. Radiat Res. 1960;12:719-727.
26. Kimeldorf D.J., Garcia J., Rubadeau D.O. Radiation-Induced Conditioned Avoidance Behavior in Rats, Mice, and Cats. Radiat Res. 1960;12:710-718.
27. Atamanyuk N.I. Effect of Medium and Low Doses of Ionizing Radiation on Higher Nervous Activity in Humans and Animals. Meditsina Ekstremal’nykh Situatsiy = Extreme Medicine. 2023;25;3:5-13 (In Russ.)
28. Mantraratnam V., Bonnet J., Rowe C., Janko D., Bolding M. X-ray Perception: Animal Studies of Sensory and Behavioral Responses to X-Rays. Front Cell Neurosci. 2022;16:917273.
29. Helo Y., Kacperek A., Rosenberg I., Royle G., Gibson A.P. The Physics of Cerenkov Light Production during Proton Therapy. Phys Med Biol. 2014;59;23:7107-7123.
PDF (RUS) Full-text article (in Russian)
Conflict of interest.The authors declare no conflict of interest.
Financing. The study had no sponsorship.
Contribution. Article was prepared with equal participation of the authors.
Article received: 20.04.2026. Accepted for publication: 25.05.2026
Medical Radiology and Radiation Safety. 2026. Vol. 71. № 5
DOI:10.33266/1024-6177-2026-71-5-13-19
D.V. Fomina1, 3, A.V. Tochilenko1, 3, T.P. Kalinin3, R.M. Sarimov4, E.O. Levintas3, A.S. Kuzmina3, S.I. Shubina3, S.A. Abdullaev1, 2, 3
EVALUATION OF THE «BYSTANDER EFFECT» WHEN INJECTING MICE WITH X-RAY-IRRADIATED OR HYDROGEN PEROXIDE-TREATED MITOCHONDRIAL DNA
1 N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia
2 Institute of Theoretical and Experimental Biophysics, Pushchino, Russia
3 A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
4 A.M. Prokhorov General Physics Institute, Moscow, Russia
Contact person: S.A. Abdullaev, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
Purpose: To assess the possibility of the “bystander effect” occurring when non-irradiated mice were injected with mitochondrial DNA irradiated with X-rays or treated with hydrogen peroxide.
Material and methods: Male Balb/c mice aged 2 months were used. Mitochondrial DNA (mtDNA) was injected intraperitoneally in saline (20 mg/mouse) – intact, irradiated at a dose of 5 Gy, and treated with hydrogen peroxide. mtDNA was isolated from mouse liver mitochondria. To purify the obtained mtDNA from nuclear DNA (nDNA) fragments, the mitochondria were treated with nuclease. Animals were sacrificed 1, 3, 7, 14, 21, and 30 days after mtDNA injection. The following parameters were then determined: mtDNA copy number in tissue cells, mitochondrial gene expression, intracellular mtDNA damage, the relative number of mutant mtDNA copies, and the level of micronuclei in cells. The brain, heart, liver, and spleen were used to analyze these parameters. Micronuclei levels were determined in bone marrow cells.
Results: Injecting mice with intact extracellular mitochondrial DNA irradiated at a dose of 5 Gy and treated with hydrogen peroxide resulted in a general pattern of changes. From the moment of injection, the mtDNA copy number in brain and heart tissues decreased by approximately 2‒3 times. In liver and spleen cells, the mtDNA copy number increased approximately 3-fold over 24 hours, and after 72 hours, the mtDNA copy number decreased to control levels. In brain and heart cells, the amount of ATP6 gene transcripts increased for up to 72 hours after injection. After 72 hours, the relative amounts of ATP6 gene transcripts in brain and heart tissues exceeded the control level by 10 and 12 times, respectively. A decrease in this parameter was then observed, with ATP6 gene transcript levels still exceeding control levels by five times 14 days after mtDNA injection. However, these changes were not considered significant due to the large standard deviation. In liver and spleen cells, ATP6 gene transcript levels increased threefold relative to control levels seven days after mtDNA injection. Changes in parameters such as mtDNA damage and mutations in these tissues, as well as micronuclei formation in bone marrow cells after mtDNA injection, did not differ significantly from control values.
Conclusion: Thus, based on the obtained research results, the hypothesis that mitochondrial extracellular DNA can cause a “bystander effect” at the level of the whole organism has not been confirmed.
Keywords: mtDNA, bystander effect, oxidative stress, X-ray exposure
For citation: Fomina DV, Tochilenko AV, Kalinin TP, Sarimov RM, Levintas EO, Kuzmina AS, Shubina SI, Abdullaev SA. Evaluation of the «Bystander Effect» when Injecting Mice with X-Ray-Irradiated or Hydrogen Peroxide-Treated Mitochondrial DNA. Medical Radiology and Radiation Safety. 2026;71(5):13–19. DOI:10.33266/1024-6177-2026-71-5-13-19
References
1.Pant G.S., Kamada N. Chromosome Aberrations in Normal Leukocytes Induced by the Plasma of Exposed Individuals. J Med Sci. 1977;26;2-3:149-154.
2.Hollowell J.G., Littlefeld L.G. Chromosome Damage Induced by Plasma of X-Rayed Patients: an Indirect Effect of X-Ray. Proc Soc Exp Biol Med. 1968;129;1:240-244. Doi: 10.3181/00379727-129-33295.
3.Littlefeld L.G., Hollowell Jr J.G., Pool Jr W.H. Chromosomal Aberrations Induced by Plasma from Irradiated Patients: an Indirect Effect of X Radiation. Further Observations and Studies of a Control Population. Radiology. 1969;93;4:879-886. Doi: 10.1148/93.4.879.
4.Marozik P., Mothersill C., Seymour C.B., Mosse I., Melnov S. Bystander Effects Induced by Serum from Survivors of the Chernobyl Accident. Exp Hematol. 2007;35;4;1:55-63. Doi: 10.1016/j.exphem.2007.01.029.
5.Emerit I., Quastel M., Goldsmith J., Merkin L., Levy A., Cernjavski L., et al. Clastogenic Factors in the Plasma of Children Exposed at Chernobyl. Mutat Res. 1997;373;1:47-54. Doi: 10.1016/s0027-5107(96)00187-x.
6.Gemignani F., Ballardin M., Maggiani F., Rossi A.M., Antonelli A., Barale R. Chromosome Aberrations in Lymphocytes and Clastogenic Factors in Plasma Detected in Belarus Children 10 Years after Chernobyl Accident. Mutat Res. 1999;446;2:245-253. Doi: 10.1016/s1383-5718(99)00194-1.
7.Nagasawa H., Little J.B. Induction of Sister Chromatid Exchanges by Extremely Low Doses of Alpha-Particles. Cancer Res. 1992;52;22:6394-6.
8.Ghosh G. Radiation-Induced Bystander Effect and Its Possible Countermeasures. J Cell Signal. 2023;4;1:13-20. Doi: 10.33696/Signaling.4.086.
9.Gilbert A., Payet V., Bernay B., Chartier-Garcia E., Testard I., Candéias S.M., Chevalier F. Label-Free Direct Mass Spectrometry Analysis of the Bystander Effects Induced in Chondrocytes by Chondrosarcoma Cells Irradiated with X-rays and Carbon Ions. Front Biosci (Landmark Ed). 2022;27;9:277. Doi: 10.31083/j.fbl2709277.
10.Vasilyeva I.N. Low-Molecular-Weight DNA in Blood Plasma as an Index of the Influence of Ionizing Radiation. Ann N Y Acad Sci. 2001;945:221-8. Doi: 10.1111/j.1749-6632.2001.tb03889.x.
11.Cooke M.S., Evans M.D., Dizdaroglu M., Lunec J. Oxidative DNA Damage: Mechanisms, Mutation, and Disease. FASEB J. 2003;17;10:1195-1214. Doi: 10.1096/fj.02-0752rev.
12.Ermakov A.V., Konkova M.S., Kostyuk S.V., Smirnova T.D., Malinovskaya E.M., Efremova L.V., Veiko N.N. An Extracellular DNA Mediated Bystander Effect Produced from Low Dose Irradiated Endothelial Cells. Mutat Res. 2011;712;1-2:1-10. Doi: 10.1016/j.mrfmmm.2011.03.002.
13.Randhawa A.K., Hawn T.R. Toll-Like Receptors: Their Roles in Bacterial Recognition and Respiratory Infections. Expert Rev Anti Infect Ther. 2008;6;4:479-495. Doi: 10.1586/14787210.6.4.479.
14.Taanman J.W. The Mitochondrial Genome: Structure, Transcription, Translation and Replication. Biochim Biophys Acta. 1999;1410;2:103-123. Doi: 10.1016/s0005-2728(98)00161-3.
15.Zhang Q., Raoof M., Chen Y., Sumi Y., Sursal T., Junger W., et al. Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury. Nature. 2010;464;7285:104-107. Doi: 10.1038/nature08780.
16.Liu Q., Wu J., Zhang X., Li X., Wu X., Zhao Y., Ren J. Circulating Mitochondrial DNA-Triggered Autophagy Dysfunction via STING Underlies Sepsis-Related Acute Lung Injury. Cell Death Dis. 2021;12;7:673. Doi: 10.1038/s41419-021-03961-9.
17.Абдуллаев С.А., Фомина Д.В., Менухов В.О., Душенко М.В., Точиленко А.В., Калинин Т.П., Евдокимовский Э.В. Изменение копийности и экспресии генов мтДНК в различных тканях мышей при локальном облучении головного мозга // Медицинская радиология и радиационная безопасность. 2025. Т.70. №2. С. 16-22 [Abdullayev S.A., Fomina D.V., Menukhov V.O., Dushenko M.V., Tochilenko A.V., Kalinin T.P., Yevdokimovskiy E.V. Changes in the Copy Number and Gene Expression of mtDNA in Various Tissues of Mice Exposed to Local Brain Irradiation. Meditsinskaya Radiologiya i Radiatsionnaya Bezopasnost’ = Medical Radiology and Radiation Safety. 2025;70;2:16–22 (In Russ.)]. Doi: 10.33266/1024-6177-2025-70-2-16-2218.
18.Abdullaev S., Gubina N., Bulanova T., Gaziev A. Assessment of Nuclear and Mitochondrial DNA, Expression of Mitochondria-Related Genes in Different Brain Regions in Rats after Whole-Body X-Ray Irradiation. Int J Mol Sci. 2020;21;4:1196. Doi: 10.3390/ijms21041196.
19.Abdullaev S.A., Glukhov S.I., Gaziev AI. Radioprotective and Radiomitigative Effects of Melatonin in Tissues with Different Proliferative Activity. Antioxidants. 2021;10:1885. Doi: 10.3390/antiox10121885.
20.Abdullaev S., Bulanova T., Timoshenko G., Gaziev A.I. Increase of mtDNA Number and its Mutant Copies in Rat Brain after Exposure to 150 MeV Protons. Mol. Biol. Reports. 2020;47:4815-4820. Doi: 10.1007/s11033-020-05491-7.
21.Abdullaev S., Minkabirova G., Karmanova E., Bruskov V., Gaziev A. Metformin Prolongs Survival Rate in Mice and Causes Increased Urinary Excretion of Cell-Free DNA in X-Irradiated Rats. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2018;831:13-18. Doi: 10.1016/j.mrgentox.2018.05.006.
22.Mothersill C., Seymour C. Radiation-Induced Bystander Effects: Past History and Future Directions. Radiat Res. 2001;155;6:759-67. Doi: 10.1667/0033-7587(2001)155[0759:ribeph]2.0.co;2.
23.Nikjoo H., Khvostunov I.K. Biophysical Model of the Radiation-Induced Bystander Effect. Int J Radiat Biol. 2003;79;1:43-52.
24.Nikjoo H., Khvostunov I.K. A Theoretical Approach to the Role and Critical Issues Associated with Bystander Effect in Risk Estimation. Hum Exp Toxicol. 2004;23(2):81=6. Doi: 10.1191/0960327104ht422oa.
25.Azzam E.I., De Toledo S.M., Spitz D.R., Little J.B. Oxidative Metabolism Modulates Signal Transduction and Micronucleus Formation in Bystander Cells from Alpha-Particle-Irradiated Normal Human Fibroblast Cultures. Cancer Res. 2002;62;19:5436-42.
26.Matsumoto H., Hamada N., Takahashi A., Kobayashi Y., Ohnishi T. Vanguards of Paradigm Shift in Radiation Biology: Radiation-Induced Adaptive and Bystander Responses. J Radiat Res. 2007;48;2:97-106. Doi: 10.1269/jrr.06090.
27.Matsumoto H., Tomita M., Otsuka K., Hatashita M., Hamada N. Nitric Oxide is a Key Molecule Serving as a Bridge between Radiation-Induced Bystander and Adaptive Responses. Curr Mol Pharmacol. 2011;4;2:126-34. Doi: 10.2174/1874467211104020126.
28.Morgan W.F. Communicating Non-Targeted Effects of Ionizing Radiation to Achieve Adaptive Homeostasis in Tissues. Curr Mol Pharmacol. 2011;4;2:135-40.
29.Ермаков А.В., Конькова М.С., Костюк С.В., Ершова Е.С., Еголина Н.А., Вейко Н.Н. Фрагменты внеклеточной ДНК из среды культивирования лимфоцитов человека, облученных в малых дозах, запускают развитие окислительного стресса и адаптивного ответа в необлученных лимфоцитах-свидетелях // Радиационная биология. Радиоэкология. 2008. Т.48. №5. С. 553-564 [Yermakov A.V., Kon’kova M.S., Kostyuk S.V., Yershova Ye.S., Yegolina N.A., Veyko N.N. Fragments of Extracellular DNA from the Culture Medium of Human Lymphocytes Irradiated in Low Doses Trigger the Development of Oxidative Stress and an Adaptive Response in Non-Irradiated Bystander Lymphocytes. Radiatsionnaya Biologiya. Radioekologiya = Radiation Biology. Radioecology. 2008;48;5:553-64 (In Russ.)].
30.Kostyuk S.V., Ermakov A.V., Alekseeva A.Y., Smirnova T.D., Glebova K.V., Efremova L.V., Baranova A., Veiko N.N. Role of Extracellular DNA Oxidative Modification in Radiation Induced Bystander Effects in Human Endotheliocytes. Mutat Res. 2012;729;1-2:52-60. Doi: 10.1016/j.mrfmmm.2011.09.005.
PDF (RUS) Full-text article (in Russian)
Conflict of interest.The authors declare no conflict of interest.
Financing. This work was supported by the Russian Science Foundation (project No. 24-24-00446).
Contribution. Article was prepared with equal participation of the authors.
Article received: 20.04.2026. Accepted for publication: 25.05.2026.
Medical Radiology and Radiation Safety. 2026. Vol. 71. № 5
DOI:10.33266/1024-6177-2026-71-5-33-39
L. Alhaddad1, S.V. Leonov2, A.N. Osipov2, 3
САNCER STEM CELLS AND THEIR POSSIBLE ROLE IN THE FAILURE OF RADIATION THERAPY
1 Department of Environmental Sciences, Faculty of Science, Damascus University, Damascus, Syria
2 Moscow Institute of Physics and Technology (National Research University), Dolgoprudny, Moscow Region, Russia
3 A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
Contact person: A.N. Osipov, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
CONTENTS
Introduction
Сancer stem cells and their possible role in tumor development and progression
Cross-talk between cancer stem cells and their niches
The influence of epithelial-mesenchymal transition
Conclusion
Keywords: cancer stem cells, сancer, radioresistance, ionizing radiation, radiation therapy
For citation: Alhaddad L, Leonov SV, Osipov AN. Саncer Stem Cells and Their Possible Role in the Failure of Radiation Therapy. Medical Radiology and Radiation Safety. 2026;71(5):33–39. DOI:10.33266/1024-6177-2026-71-5-33-39
References
1. Eyler C.E., Rich J.N. Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis. Journal of Clinical Oncology. 2008;26;17:2839-45. Doi: 10.1200/JCO.2007.15.1829.
2. Fujiwara T., Bandi M., Nitta M., Ivanova E.V., Bronson R.T., Pellman D. Cytokinesis Failure Generating Tetraploids Promotes Tumorigenesis in p53-Null Cells. Nature. 2005;437;7061:1043-7. Doi: 10.1038/nature04217.
3. Замулаева И.А., Матчук О.Н., Селиванова Е.И., Андреев В.Г., Липунов Н.М., Макаренко С.А. и др. Увеличение количества опухолевых стволовых клеток под воздействием редкоионизирующего излучения // Радиационная биология. Радиоэкология. 2014. Т.54. №3. С. 256-264 [Zamulayeva I.A., Matchuk O.N., Selivanova Ye.I., Andreyev V.G., Lipunov N.M., Makarenko S.A., et al. Increase in the Number of Tumor Stem Cells under the Influence of Rare-Ionizing Radiation. Radiatsionnaya Biologiya. Radioekologiya = Radiation Biology. Radioecology. 2014;54;3:256–64 (In Russ)]. Doi: 10.7868/S0869803114030187.
4. Snijder B., Pelkmans L. Origins of Regulated Cell-to-Cell Variability. Nature Reviews Molecular Cell Biology. 2011;12;2:119-25. Doi: 10.1038/nrm3044.
5. Inda M.M., Bonavia R., Mukasa A., Narita Y., Sah D.W., Vandenberg S., et al. Tumor Heterogeneity is an Active Process Maintained by a Mutant EGFR-Induced Cytokine Circuit in Glioblastoma. Genes & Development. 2010;24;16:1731-45. Doi: 10.1101/gad.1890510.
6. Heppner G.H. Tumor Heterogeneity. Cancer Research. 1984;44;6:2259-65.
7. McQuerry J.A., Chang J.T., Bowtell D.D.L., Cohen A., Bild A.H. Mechanisms and Clinical Implications of Tumor Heterogeneity and Convergence on Recurrent Phenotypes. Journal of Molecular Medicine. 2017;95;11:1167-78. Doi: 10.1007/s00109-017-1587-4.
8. Visvader J.E. Cells of Origin in Cancer. Nature. 2011;469;7330:314-22. Doi: 10.1038/nature09781.
9. Lim Z.F., Ma P.C. Emerging Insights of Tumor Heterogeneity and Drug Resistance Mechanisms in Lung Cancer Targeted Therapy. Journal of Hematology & Oncology. 2019;12;1:134. Doi: 10.1186/s13045-019-0818-2.
10. Rich J.N. Cancer Stem Cells: Understanding Tumor Hierarchy and Heterogeneity. Medicine. 2016;95;1 Suppl 1:S2-S7. Doi: 10.1097/MD.0000000000004764.
11. Puhr M., Hoefer J., Schafer G., Erb H.H., Oh S.J., Klocker H., et al. Epithelial-to-Mesenchymal Transition Leads to Docetaxel Resistance in Prostate Cancer and is Mediated by Reduced Expression of miR-200c and miR-205. The American Journal of Pathology. 2012;181;6:2188-201. Doi: 10.1016/j.ajpath.2012.08.011.
12. 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. Doi: 10.3390/ijms232113577.
13. Eramo A., Lotti F., Sette G., Pilozzi E., Biffoni M., Di Virgilio A., et al. Identification and Expansion of the Tumorigenic Lung Cancer Stem Cell Population. Cell Death and Differentiation. 2008;15;3:504-14. Doi: 10.1038/sj.cdd.4402283.
14. Kendall S.E., Najbauer J., Johnston H.F., Metz M.Z., Li S., Bowers M., et al. Neural Stem Cell Targeting of Glioma is Dependent on Phosphoinositide 3-Kinase Signaling. Stem Cells. 2008;26;6:1575-86. Doi: 10.1634/stemcells.2007-0887.
15. Hamburger A.W., Salmon S.E. Primary Bioassay of Human Tumor Stem Cells. Science. 1977;197;4302:461-3. Doi: 10.1126/science.560061.
16. Han J., Won M., Kim J.H., Jung E., Min K., Jangili P., et al. Cancer Stem Cell-Targeted Bio-Imaging and Chemotherapeutic Perspective. Chemical Society Reviews. 2020;49;22:7856-78. Doi: 10.1039/d0cs00379d.
17. Alkon N., Ivanova A., Frolova E., Chumakov S. Cancer Stem Cells as Therapeutic Targets. Genes and Cells. 2018;13;2:25–34.
18. Clarke M.F., Fuller M. Stem Cells and Cancer: Two Faces of Eve. Cell. 2006;124;6:1111-5. Doi: 10.1016/j.cell.2006.03.011.
19. Reya T., Morrison S.J., Clarke M.F., Weissman I.L. Stem Cells, Cancer, and Cancer Stem Cells. Nature. 2001;414;6859:105-11. Doi: 10.1038/35102167.
20. Liu Y., Yang M., Luo J., Zhou H. Radiotherapy Targeting Cancer Stem Cells «Awakens» them to Induce Tumour Relapse and Metastasis in Oral Cancer. International Journal of Oral Science. 2020;12;1:19. Doi: 10.1038/s41368-020-00087-0.
21. Chang L., Graham P., Hao J., Ni J., Deng J., Bucci J., et al. Cancer Stem Cells and Signaling Pathways in Radioresistance. Oncotarget. 2016;7;10:11002-17. Doi: 10.18632/oncotarget.6760.
22. Mirantes C., Espinosa I., Ferrer I., Dolcet X., Prat J., Matias-Guiu X. Epithelial-to-Mesenchymal Transition and Stem Cells in Endometrial Cancer. Human Pathology. 2013;44;10:1973-81. Doi: 10.1016/j.humpath.2013.04.009.
23. Пучинская М.В. Маркеры стволовых опухолевых клеток и их прогностическое значение // Архив патологии. 2016. Т.78. №2. С. 47–54 [Puchinskaya M.V. Cancer Stem Cell Markers and their Prognostic Value. Arkhiv Patologii = Russian Journal of Archive of Patology. 2016;78;2:47-54 (In Russ.)]. Doi: 10.17116/patol201678247-54.
24. Kong Y., Yoshida S., Saito Y., Doi T., Nagatoshi Y., Fukata M., et al. CD34+CD38+CD19+ as Well as CD34+CD38-CD19+ Cells are Leukemia-Initiating Cells with Self-Renewal Capacity in Human B-Precursor ALL. Leukemia. 2008;22;6:1207-13. Doi: 10.1038/leu.2008.83.
25. Singh S.K., Clarke I.D., Terasaki M., Bonn V.E., Hawkins C., Squire J., et al. Identification of a Cancer Stem Cell in Human Brain Tumors. Cancer Research. 2003;63;18:5821-8.
26. Pustovalova M, Blokhina T, Alhaddad L, Chigasova A, Chuprov-Netochin R, Veviorskiy A, et al. CD44+ and CD133+ Non-Small Cell Lung Cancer Cells Exhibit DNA Damage Response Pathways and Dormant Polyploid Giant Cancer Cell Enrichment Relating to Their p53 Status. International Journal of Molecular Sciences. 2022;23;9. Doi: 10.3390/ijms23094922.
27. Ponti D., Costa A., Zaffaroni N., Pratesi G., Petrangolini G., Coradini D., et al. Isolation and in vitro Propagation of Tumorigenic Breast Cancer Cells with Stem/Progenitor Cell Properties. Cancer Research. 2005;65;13:5506-11. Doi: 10.1158/0008-5472.CAN-05-0626.
28. Pustovalova M., Alhaddad L., Blokhina T., Smetanina N., Chigasova A., Chuprov-Netochin R., et al. The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status. International Journal of Molecular Sciences. 2021;22;5:2369. Doi: 10.3390/ijms22052369.
29. Collins A.T., Berry P.A., Hyde C., Stower M.J., Maitland N.J. Prospective Identification of Tumorigenic Prostate Cancer Stem Cells. Cancer Research. 2005;65;23:10946-51. Doi: 10.1158/0008-5472.CAN-05-2018.
30. Ricci-Vitiani L., Lombardi D.G., Pilozzi E., Biffoni M., Todaro M., Peschle C., et al. Identification and Expansion of Human Colon-Cancer-Initiating Cells. Nature. 2007;445;7123:111-5. Doi: 10.1038/nature05384.
31. Hirschmann-Jax C., Foster A.E., Wulf G.G., Nuchtern J.G., Jax T.W., Gobel U., et al. A Distinct “Side Population” of Cells with High drug Efflux Capacity in Human Tumor Cells. Proceedings of the National Academy of Sciences of the United States of America. 2004;101;39:14228-33. Doi: 10.1073/pnas.0400067101.
32. Jiang F., Qiu Q., Khanna A., Todd N.W., Deepak J., Xing L., et al. Aldehyde Dehydrogenase 1 is a Tumor Stem Cell-Associated Marker in Lung Cancer. Molecular Cancer Research. 2009;7;3:330-8. Doi: 10.1158/1541-7786.MCR-08-0393.
33. Tirino V., Camerlingo R., Franco R., Malanga D., La Rocca A., Viglietto G., et al. The Role of CD133 in the Identification and Characterisation of Tumour-Initiating Cells in Non-Small-Cell Lung Cancer. European Journal of Cardio-Thoracic Surgery. 2009;36;3:446-53. Doi: 10.1016/j.ejcts.2009.03.063.
34. Huang Z., Cheng L., Guryanova O.A., Wu Q., Bao S. Cancer Stem Cells in Glioblastoma--Molecular Signaling and Therapeutic Targeting. Protein & Cell. 2010;1;7:638-55. Doi: 10.1007/s13238-010-0078-y.
35. Gilbert C.A., Ross A.H. Glioma Stem Cells: Cell Culture, Markers and Targets for New Combination Therapies. Cancer Stem Cells Theories and Practice. Rijeka, IntechOpen, 2011. P. 3-22.
36. Cole M.F., Johnstone S.E., Newman J.J., Kagey M.H., Young R.A. Tcf3 is an Integral Component of the Core Regulatory Circuitry of Embryonic Stem Cells. Genes & Development. 2008;22;6:746-55. Doi: 10.1101/gad.1642408.
37. Hu Q., Zhang L., Wen J., Wang S., Li M., Feng R., et al. The EGF Receptor-Sox2-EGF Receptor Feedback Loop Positively Regulates the self-Renewal of Neural Precursor Cells. Stem Cells. 2010;28;2:279-86. Doi: 10.1002/stem.246.
38. Ikushima H., Todo T., Ino Y., Takahashi M., Miyazawa K., Miyazono K. Autocrine TGF-Beta Signaling Maintains Tumorigenicity of Glioma-Initiating Cells Through SRY-Related HMG-Box Factors. Cell Stem Cell. 2009;5;5:504-14. Doi: 10.1016/j.stem.2009.08.018.
39. Marson A., Foreman R., Chevalier B., Bilodeau S., Kahn M., Young R.A., et al. Wnt Signaling Promotes Reprogramming of Somatic Cells to Pluripotency. Cell Stem Cell. 2008;3;2:132-5. Doi: 10.1016/j.stem.2008.06.019.
40. Po A., Ferretti E., Miele E., De Smaele E., Paganelli A., Canettieri G., et al. Hedgehog Controls Neural Stem Cells through p53-Independent Regulation of Nanog. The EMBO Journal. 2010;29;15:2646-58. Doi: 10.1038/emboj.2010.131.
41. Song I.S., Jeong Y.J., Han J. Mitochondrial Metabolism in Cancer Stem Cells: a Therapeutic Target for Colon Cancer. BMB Reports. 2015;48;10:539-40. Doi: 10.5483/bmbrep.2015.48.10.179.
42. Johannessen T.C., Bjerkvig R., Tysnes B.B. DNA Repair and Cancer Stem-Like Cells--Potential Partners in Glioma drug Resistance? Cancer Treatment Reviews. 2008;34;6:558-67. Doi: 10.1016/j.ctrv.2008.03.125.
43. Al-Hajj M., Becker M.W., Wicha M., Weissman I., Clarke M.F. Therapeutic Implications of Cancer Stem Cells. Current Opinion in Genetics & Development. 2004;14;1:43-7. Doi: 10.1016/j.gde.2003.11.007.
44. Hemmati H.D., Nakano I., Lazareff J.A., Masterman-Smith M., Geschwind D.H., Bronner-Fraser M., et al. Cancerous Stem Cells Can Arise from Pediatric Brain Tumors. Proceedings of the National Academy of Sciences of the United States of America. 2003;100;25:15178-83. Doi: 10.1073/pnas.2036535100.
45. Lee S.Y., Jeong E.K., Ju M.K., Jeon H.M., Kim M.Y., Kim C.H., et al. Induction of Metastasis, Cancer Stem Cell Phenotype, and Oncogenic Metabolism in Cancer Cells by Ionizing Radiation. Molecular Cancer. 2017;16;1:10. Doi: 10.1186/s12943-016-0577-4.
46. Никифорова З.Н., Кудрявцев И.А., Арноцкая Н.Е., Брюховецкий И.С., Шевченко В.Е. Опухолевые стволовые клетки мультиформной глиобластомы // Успехи молекулярной онкологии. 2016. Т.3. №2. С. 26–33. [Nikiforova Z.N., Kudryavtsev I.A., Arnotskaya N.Ye., Bryukhovetskiy I.S., Shevchenko V.Ye. Tumor Stem Cells of Glioblastoma Multiforme. Uspekhi Molekulyarnoy Onkologii = Advances in Molecular Oncology. 2016;3;2:26-33 (In Russ.)].
47. Oskarsson T., Batlle E., Massague J. Metastatic Stem Cells: Sources, Niches, and Vital Pathways. Cell Stem Cell. 2014;14;3:306-21. Doi: 10.1016/j.stem.2014.02.002.
48. Ye J., Wu D., Wu P., Chen Z., Huang J. The Cancer Stem Cell Niche: Cross Talk between Cancer Stem Cells and Their Microenvironment. Tumour Biology. 2014;35;5:3945-51. Doi: 10.1007/s13277-013-1561-x.
49. Plaks V., Kong N., Werb Z. The Cancer Stem Cell Niche: how Essential is the Niche in Regulating Stemness of Tumor Cells? Cell Stem Cell. 2015;16;3:225-38. Doi: 10.1016/j.stem.2015.02.015.
50. Pozdnyakov D., Shuvalov O., Barlev N., Mittenberg A. Transcription Factor ZEB1: Post-Transcriptional Regulation of its Activity in Human Breast Carcinomas. Cytology. 2020;62;1:3-15.
51. Mani S.A., Guo W., Liao M.J., Eaton E.N., Ayyanan A., Zhou A.Y., et al. The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells. Cell. 2008;133;4:704-15. Doi: 10.1016/j.cell.2008.03.027.
52. Kotiyal S., Bhattacharya S. Breast Cancer Stem Cells, EMT and Therapeutic Targets. Biochemical and Biophysical Research Communications. 2014;453;1:112-6. Doi: 10.1016/j.bbrc.2014.09.069.
53. Dezso Z., Oestreicher J., Weaver A., Santiago S., Agoulnik S., Chow J., et al. Gene Expression Profiling Reveals Epithelial Mesenchymal Transition (EMT) Genes can Selectively Differentiate Eribulin Sensitive Breast Cancer Cells. PloS One. 2014;9;8:e106131. Doi: 10.1371/journal.pone.0106131.
54. Kalluri R., Weinberg R.A. The Basics of Epithelial-Mesenchymal Transition. The Journal of Clinical Investigation. 2009;119;6:1420-8. Doi: 10.1172/JCI39104.
55. Caramel J., Papadogeorgakis E., Hill L., Browne G.J., Richard G., Wierinckx A., et al. A Switch in the Expression of Embryonic EMT-Inducers Drives the Development of Malignant Melanoma. Cancer Cell. 2013;24;4:466-80. Doi: 10.1016/j.ccr.2013.08.018.
56. Byers L.A., Diao L., Wang J., Saintigny P., Girard L., Peyton M., et al. An Epithelial-Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance. Clinical Cancer Research. 2013;19;1:279-90. Doi: 10.1158/1078-0432.CCR-12-1558.
57. Takebe N., Miele L., Harris P.J., Jeong W., Bando H., Kahn M., et al. Targeting Notch, Hedgehog, and Wnt Pathways in Cancer Stem Cells: Clinical Update. Nature Reviews Clinical Oncology. 2015;12;8:445-64. Doi: 10.1038/nrclinonc.2015.61.
58. Arumugam T., Ramachandran V., Fournier K.F., Wang H., Marquis L., Abbruzzese J.L., et al. Epithelial to Mesenchymal Transition Contributes to Drug Resistance in Pancreatic Cancer. Cancer Research. 2009;69;14:5820-8. Doi: 10.1158/0008-5472.CAN-08-2819.
59. Gonzalez-Moreno O., Lecanda J., Green J.E., Segura V., Catena R., Serrano D., et al. VEGF el|Icits Epithelial-Mesenchymal Transition (EMT) in Prostate Intraepithelial Neoplasia (PIN)-Like Cells Via an Autocrine Loop. Experimental Cell Research. 2010;316;4:554-67. Doi: 10.1016/j.yexcr.2009.11.020.
60. Khromova N., Kopnin P., Rybko V., Kopnin B.P. Downregulation of VEGF-C Expression in Lung and Colon Cancer Cells Decelerates Tumor Growth and Inhibits Metastasis Via Multiple Mechanisms. Oncogene. 2012;31;11:1389-97. Doi: 10.1038/onc.2011.330.
61. Yi Z.Y., Feng L.J., Xiang Z., Yao H. Vascular Endothelial Growth Factor Receptor-1 Activation Mediates Epithelial to Mesenchymal Transition in Hepatocellular Carcinoma Cells. Journal of Investigative Surgery. 2011;24;2:67-76. Doi: 10.3109/08941939.2010.542272.
62. Brabletz T., Hlubek F., Spaderna S., Schmalhofer O., Hiendlmeyer E., Jung A., et al. Invasion and Metastasis in Colorectal Cancer: Epithelial-Mesenchymal Transition, Mesenchymal-Epithelial Transition, Stem Cells and Beta-Catenin. Cells, Tissues, Organs. 2005;179;1-2:56-65. Doi: 10.1159/000084509.
63. Ortensi B., Setti M., Osti D., Pelicci G. Cancer Stem Cell Contribution to Glioblastoma Invasiveness. Stem Cell Research & Therapy. 2013;4;1:18. Doi: 10.1186/scrt166.
64. Heldin C.H., Landstrom M., Moustakas A. Mechanism of TGF-Beta Signaling to Growth Arrest, Apoptosis, and Epithelial-Mesenchymal Transition. Current Opinion in Cell Biology. 2009;21;2:166-76. Doi: 10.1016/j.ceb.2009.01.021.
65. Mallini P., Lennard T., Kirby J., Meeson A. Epithelial-to-Mesenchymal Transition: what is the Impact on Breast Cancer Stem Cells and drug Resistance. Cancer Treatment Reviews. 2014;40;3:341-8. Doi: 10.1016/j.ctrv.2013.09.008.
66. Фармаковская М.Д., Хромова Н.В., Рыбко В.А., Копнин П.Б. Роль эпителиально-мезенхимального перехода в регуляции свойств раковых стволовых клеток солидных опухолей // Российский биотерапевтический журнал. 2015. Т.14. №4. С. 3-8 [Farmakovskaya M.D., Khromova N.V., Rybko V.A., Kopnin P.B. The Role of Epithelial-Mesenchymal Transition in Regulating the Properties of Cancer Stem Cells of Solid Tumors. Rossiyskiy Bioterapevticheskiy Zhurnal = Russian Journal of Biotherapeutics. 2015;14;4:3-8 (In Russ.)].
67. Kurrey N.K., Jalgaonkar S.P., Joglekar A.V., Ghanate A.D., Chaskar P.D., Doiphode R.Y., et al. Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53-Mediated Apoptosis and Acquiring a Stem-Like Phenotype in Ovarian Cancer Cells. Stem Cells. 2009;27;9:2059-68. Doi: 10.1002/stem.154.
68. Zhang X., Wu J., Luo S., Lechler T., Zhang J.Y. FRA1 Promotes Squamous Cell Carcinoma Growth and Metastasis through Distinct AKT and c-JUN Dependent Mechanisms. Oncotarget. 2016;7;23:34371-83. Doi: 10.18632/oncotarget.9110.
69. Diesch J., Sanij E., Gilan O., Love C., Tran H., Fleming N.I., et al. Widespread FRA1-Dependent Control of Mesenchymal Transdifferentiation Programs in Colorectal Cancer Cells. PloS One. 2014;9;3:e88950. Doi: 10.1371/journal.pone.0088950.
70. Zhang L., Liu H., Mu X., Cui J., Peng Z. Dysregulation of Fra1 Expression by Wnt/Beta-Catenin Signalling Promotes Glioma Aggressiveness through Epithelial-Mesenchymal Transition. Bioscience Reports. 2017;37;2:BSR20160643. Doi: 10.1042/BSR20160643.
71. Risolino M., Mandia N., Iavarone F., Dardaei L., Longobardi E., Fernandez S., et al. Transcription Factor PREP1 Induces EMT and Metastasis by Controlling the TGF-Beta-SMAD3 Pathway in Non-Small Cell Lung Adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2014;111;36:E3775-84. Doi: 10.1073/pnas.1407074111.
72. Usui A., Hoshino I., Akutsu Y., Sakata H., Nishimori T., Murakami K., et al. The Molecular Role of Fra-1 and its Prognostic Significance in Human Esophageal Squamous Cell Carcinoma. Cancer. 2012;118;13:3387-96. Doi: 10.1002/cncr.26652.
73. Lu D., Chen S., Tan X., Li N., Liu C., Li Z., et al. Fra-1 Promotes Breast Cancer Chemosensitivity by Driving Cancer Stem Cells from Dormancy. Cancer Research. 2012;72;14:3451-6. Doi: 10.1158/0008-5472.CAN-11-2536.
74. Sayan A.E., Stanford R., Vickery R., Grigorenko E., Diesch J., Kulbicki K., et al. Fra-1 Controls Motility of Bladder Cancer Cells via Transcriptional Upregulation of the Receptor Tyrosine Kinase AXL. Oncogene. 2012;31;12:1493-503. Doi: 10.1038/onc.2011.336.
75. Zhong G., Chen X., Fang X., Wang D., Xie M., Chen Q. Fra-1 is Upregulated in Lung Cancer Tissues and Inhibits the Apoptosis of Lung Cancer Cells by the P53 Signaling Pathway. Oncology Reports. 2016;35;1:447-53. Doi: 10.3892/or.2015.4395.
76. Gomez-Casal R., Bhattacharya C., Ganesh N., Bailey L., Basse P., Gibson M., et al. Non-Small Cell Lung Cancer Cells Survived Ionizing Radiation Treatment Display Cancer Stem Cell and Epithelial-Mesenchymal Transition Phenotypes. Molecular Cancer. 2013;12;1:94. Doi: 10.1186/1476-4598-12-94.
77. Siebzehnrubl F.A., Silver D.J., Tugertimur B., Deleyrolle L.P., Siebzehnrubl D., Sarkisian M.R., et al. The ZEB1 Pathway Links Glioblastoma Initiation, Invasion and Chemoresistance. EMBO Molecular Medicine. 2013;5;8:1196-212. Doi: 10.1002/emmm.201302827.
78. Plaks V., Kong N., Werb Z. The Cancer Stem Cell Niche: how Essential is the Niche in Regulating Stemness of Tumor Cells? Cell Stem Cell. 2015;16;3:225-38. Doi: 10.1016/j.stem.2015.02.015.
PDF (RUS) Full-text article (in Russian)
Conflict of interest.The authors declare no conflict of interest.
Financing. The research was supported by the Russian Science Foundation (project No. 24-45-20002, https://rscf.ru/project/24-45-20002/).
Contribution. L. Alhaddad: writing – original draft preparation and editing; A.N. Osipov and S.V. Leonov: conceptualization, writing ‒ review and editing.
Article received: 20.04.2026. Accepted for publication: 25.05.2026.
Medical Radiology and Radiation Safety. 2026. Vol. 71. № 5
DOI:10.33266/1024-6177-2026-71-5-20-32
G.G. Golyshev1, K.V. Tikunova1, Y. Deeni2, A.N. Goltsov1
ENHANCING TUMOUR RADIOSENSITIVITY BY TARGETING NRF2 ANTIOXIDANT SYSTEM
1 MIREA - Russian Technological University, Moscow, Russia
2 Federal University Dutse, Dutse, Nigeria
Contact person: Alexey Goltsov, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
The challenge of radioresistance in radiotherapy is currently tackled by introducing new radiotherapy facilities with high-quality of ionizing beams, high-precision of radiation delivery to tumour, and optimized treatment plans. This strategy is further enhanced by the development of new therapeutic methods for suppressing radioresistance in tumours of cancer patients by combining radiotherapy with chemo-, immuno-, and targeted therapies tailored to patients’ molecular profiles. As a result of numerous preclinical and clinical trials of the combination therapy, the primary molecular mechanisms, driving an increase in radiosensitivity, and the key cellular signalling pathways responsible for radioresistance were identified. One of the established radioresistance mechanisms involves adaptation of cancer cells to an elevated levels of reactive oxygen species (ROS) by activating antioxidant systems (AOS) of cellular protection and survival. Since radiotherapy mainly relies on ROS production that damages DNA, causing cancer cell death, activation of the AOS can mitigate radiotherapy effectiveness. Therefore, suppressing the AOS and its associated adaptation mechanisms may increase tumour radiosensitivity and enhance treatment outcomes.
In this review, we discuss the role of one of the key components of the cellular AOS which is under the control of the NRF2 transcription factor (nuclear erythroid factor 2) – a master regulator of cellular redox balance that protects cells from oxidative stress during radiotherapy by governing expression of a battery of antioxidant enzymes. We first outline the molecular mechanism of the redox-sensitive NRF2 AOS and its activation in response to the increased ROS levels following irradiation. We then evaluate experimental and clinical evidence regarding NRF2 activation in various cancer cells and tumours exposed to ionizing irradiation. Furthermore, we discuss results of numerous experimental and clinical investigations demonstrating that suppression of the NRF2 AOS enhances radiosensitivity of various cancers and improves radiotherapy outcomes. Collectively, these findings confirmed the potential of combining radiotherapy with targeted therapy aiming at the suppression of the NRF2 AOS. In this combination therapy NRF2 inhibitors act as radiosensitizers that promote overcoming radioresistance due to extra ROS accumulation and oxidative stress induction in cancer cells by inhibition of the NRF2-dependent antioxidant responses to radiotherapy.
Keywords: transcription factor NRF2, radiotherapy, radioresistance, radiosensitizer, antioxidant system, targeted therapy
For citation: Golyshev GG, Tikunova KV, Deeni Y, Goltsov AN. Enhancing Tumour Radiosensitivity by Targeting Nrf2 Antioxidant System. Medical Radiology and Radiation Safety. 2026;71(5):20–32. DOI:10.33266/1024-6177-2026-71-5-20-32
References
1. Meehan J, Gray M, Martínez-Pérez C, Kay C, Pang LY, Fraser JA, Poole AV, Kunkler IH, Langdon SP, Argyle D, Turnbull AK. Precision Medicine and the Role of Biomarkers of Radiotherapy Response in Breast Cancer. Front Oncol. 2020;10:628. doi:10.3389/fonc.2020.00628 PubMed PMID: 32391281; PubMed Central PMCID: PMC7193869.
2. Barker HE, Paget JTE, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015 Jul;15(7):409–25. doi:10.1038/nrc3958 PubMed PMID: 26105538; PubMed Central PMCID: PMC4896389.
3. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative Stress in Cancer. Cancer Cell. 2020 Aug 10;38(2):167–97. doi:10.1016/j.ccell.2020.06.001.
4. Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, Castoria G, Migliaccio A. ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 2020 Feb;52(2):192–203. doi:10.1038/s12276-020-0384-2 PubMed PMID: 32060354; PubMed Central PMCID: PMC7062874.
5. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018 Jul 9;34(1):21–43. doi:10.1016/j.ccell.2018.03.022 PubMed PMID: 29731393; PubMed Central PMCID: PMC6039250.
6. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A. Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev. 2017;2017:8416763. doi:10.1155/2017/8416763 PubMed PMID: 28819546; PubMed Central PMCID: PMC5551541.
7. Oshi M, Gandhi S, Yan L, Tokumaru Y, Wu R, Yamada A, Matsuyama R, Endo I, Takabe K. Abundance of reactive oxygen species (ROS) is associated with tumor aggressiveness, immune response and worse survival in breast cancer. Breast cancer research and treatment. 2022 May 31;194(2):231. doi:10.1007/s10549-022-06633-0 PubMed PMID: 35639264.
8. Glorieux C, Liu S, Trachootham D, Huang P. Targeting ROS in cancer: rationale and strategies. Nat Rev Drug Discov. 2024 Aug;23(8):583–606. doi:10.1038/s41573-024-00979-4.
9. Baird L, Yamamoto M. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. Mol Cell Biol. 2020 Jun 15;40(13):e00099-20. doi:10.1128/MCB.00099-20 PubMed PMID: 32284348; PubMed Central PMCID: PMC7296212.
10. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes to Cells: Devoted to Molecular & Cellular Mechanisms. 2011 Feb;16(2):123–40. doi:10.1111/j.1365-2443.2010.01473.x PubMed PMID: 21251164.
11. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of Nrf2 in cancer. Pharmacological research : the official journal of the Italian Pharmacological Society. 2008;58(5–6):262–70. doi:10.1016/j.phrs.2008.09.003 PubMed PMID: 18838122.
12. Kobayashi H, Imanaka S, Shigetomi H. Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis. Oncology letters. 2022 Mar 1;23:80. doi:10.3892/ol.2022.13200.
13. Kitamura H, Motohashi H. NRF2 addiction in cancer cells. Cancer Sci. 2018 Apr;109(4):900–11. doi:10.1111/cas.13537 PubMed PMID: 29450944; PubMed Central PMCID: PMC5891176.
14. Okazaki K, Papagiannakopoulos T, Motohashi H. Metabolic features of cancer cells in NRF2 addiction status. Biophys Rev. 2020 Feb 28;12(2):435–41. doi:10.1007/s12551-020-00659-8 PubMed PMID: 32112372; PubMed Central PMCID: PMC7242251.
15. Tufekci KU, Civi Bayin E, Genc S, Genc K. The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson’s Disease. Parkinsons Dis. 2011 Feb 22;2011:314082. Located at: C:Nrf2RefNRF2 Therapy. doi:10.4061/2011/314082 PubMed PMID: 21403858; PubMed Central PMCID: PMC3049335.
16. Mirzaei S, Zarrabi A, Hashemi F, Zabolian A, Saleki H, Azami N, Hamzehlou S, Farahani MV, Hushmandi K, Ashrafizadeh M, Khan H, Kumar AP. Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery. Antioxidants (Basel). 2021 Feb 26;10(3):349. Located at: C:Nrf2RefNRF2 Therapy. doi:10.3390/antiox10030349 PubMed PMID: 33652780; PubMed Central PMCID: PMC7996755.
17. Boutten A, Goven D, Artaud-Macari E, Boczkowski J, Bonay M. NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease. Trends Mol Med. 2011 Jul;17(7):363–71. Located at: C:Nrf2RefNRF2 Therapy. doi:10.1016/j.molmed.2011.02.006 PubMed PMID: 21459041.
18. Dinkova-Kostova AT, Copple IM. Advances and challenges in therapeutic targeting of NRF2. Trends in Pharmacological Sciences. 2023 Mar 1;44(3):137–49. doi:10.1016/j.tips.2022.12.003 PubMed PMID: 36628798.
19. Li Y, Zhang X, Wang Z, Li B, Zhu H. Modulation of redox homeostasis: A strategy to overcome cancer drug resistance. Front Pharmacol. 2023 Mar 22;14. doi:10.3389/fphar.2023.1156538
20. Copple IM. The Keap1-Nrf2 cell defense pathway--a promising therapeutic target? Adv Pharmacol. 2012;63:43–79. doi:10.1016/B978-0-12-398339-8.00002-1 PubMed PMID: 22776639.
21. Lu MC, Ji JA, Jiang ZY, You QD. The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update. Med Res Rev. 2016 Sep;36(5):924–63. doi:10.1002/med.21396 PubMed PMID: 27192495.
22. Zhan X, Li J, Zhou T. Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas. Front Pharmacol. 2021 Mar 24;12. doi:10.3389/fphar.2021.565748.
23. Zhang J, Xu HX, Zhu JQ, Dou YX, Xian YF, Lin ZX. Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment. Int J Biol Sci. 2023 Jun 4;19(10):3029–41. doi:10.7150/ijbs.82401 PubMed PMID: 37416770; PubMed Central PMCID: PMC10321279.
24. Zenkov NK, Menshchikova EB, Tkachev VO. Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target diseases. Biochemistry (Moscow). 2013;78(1):27–47.
25. Marampon F, Codenotti S, Megiorni F, Del Fattore A, Camero S, Gravina GL, Festuccia C, Musio D, De Felice F, Nardone V, Santoro AN, Dominici C, Fanzani A, Pirtoli L, Fioravanti A, Tombolini V, Cheleschi S, Tini P. NRF2 orchestrates the redox regulation induced by radiation therapy, sustaining embryonal and alveolar rhabdomyosarcoma cells radioresistance. Journal of Cancer Research and Clinical Oncology. 2019 Apr;145(4):881–93. doi:10.1007/s00432-019-02851-0.
26. Golyshev GG, Tikunova KV, Zaytsev OA, Deene Y, Goltsov AN. NRF2 antioxidant cellular system as a therapeutic target for enhancing cancer radiosensitivity. Medical Physics. 2025;(1):94–109. doi:10.52775/1810-200X-2025-105-1-94-109.
27. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. Dimerization of Substrate Adaptors Can Facilitate Cullin-mediated Ubiquitylation of Proteins by a “Tethering” Mechanism:
A TWO-SITE INTERACTION MODEL FOR THE Nrf2-Keap1 COMPLEX*. Journal of Biological Chemistry. 2006 Aug 25;281(34):24756–68. doi:10.1074/jbc.M601119200.
28. Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med. 2015 Nov;88(Pt B):93–100. doi:10.1016/j.freeradbiomed.2015.06.006 PubMed PMID: 26117331.
29. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends in Biochemical Sciences. 2014 Apr;39(4):199–218. doi:10.1016/j.tibs.2014.02.002 PubMed PMID: 24647116.
30. Apopa PL, He X, Ma Q. Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol. 2008 Feb;22(1):63–76. doi:10.1002/jbt.20212 PubMed PMID: 18273910.
31. Liu T, Lv YF, Zhao JL, You QD, Jiang ZY. Regulation of Nrf2 by phosphorylation: Consequences for biological function and therapeutic implications. Free Radical Biology and Medicine. 2021 May 20;168:129–41. doi:10.1016/j.freeradbiomed.2021.03.034.
32. Kaspar JW, Jaiswal AK. Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression. FASEB J. 2011 Mar;25(3):1076–87. doi:10.1096/fj.10-171553 PubMed PMID: 21097520; PubMed Central PMCID: PMC3042843.
33. Zhang Q, Pi J, Woods CG, Andersen ME. A systems biology perspective on Nrf2-mediated antioxidant response. Toxicol Appl Pharmacol. 2010 Apr 1;244(1):84–97. doi:10.1016/j.taap.2009.08.018 PubMed PMID: 19716833; PubMed Central PMCID: PMC2837757.
34. Liu S, Pi J, Zhang Q. Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway. Redox Biol. 2022 Aug;54:102389. doi:10.1016/j.redox.2022.102389 PubMed PMID: 35792437; PubMed Central PMCID: PMC9287733.
35. Khalil HS, Goltsov A, Langdon SP, Harrison DJ, Bown J, Deeni Y. Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells. Journal of Biotechnology. 2015 May;202:12–30. doi:10.1016/J.JBIOTEC.2014.09.027 PubMed PMID: 25449014.
36. Kawasaki Y, Okumura H, Uchikado Y, Kita Y, Sasaki K, Owaki T, Ishigami S, Natsugoe S. Nrf2 is Useful for Predicting the Effect of Chemoradiation Therapy on Esophageal Squamous Cell Carcinoma. Annals of Surgical Oncology. 2014 Jul 1;21(7):2347–52. doi:10.1245/s10434-014-3600-2.
37. Singh A, Bodas M, Wakabayashi N, Bunz F, Biswal S. Gain of Nrf2 Function in Non-Small-Cell Lung Cancer Cells Confers Radioresistance. Antioxidants & Redox Signaling. 2010 Dec;13(11):1627–37. doi:10.1089/ars.2010.3219.
38. Tang T, Jia Y, Liang H, Han Y, Cong Z, Wang H, Ji X. Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia. Transl Cancer Res. 2022 Nov;11(11):4105–16. doi:10.21037/tcr-22-1420 PubMed PMID: 36523295; PubMed Central PMCID: PMC9745379.
39. McMahon SJ. The linear quadratic model: usage, interpretation and challenges. Phys Med Biol. 2018 Dec 19;64(1):01TR01. doi:10.1088/1361-6560/aaf26a PubMed PMID: 30523903.
40. Xia D, Zhang XR, Ma YL, Zhao ZJ, Zhao R, Wang YY. Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKIIα-associated activation of autophagy. Cell & Bioscience. 2020 Jul 30;10(1):90. doi:10.1186/s13578-020-00456-6.
41. McDonald JT, Kim K, Norris AJ, Vlashi E, Phillips TM, Lagadec C, Della Donna L, Ratikan J, Szelag H, Hlatky L, McBride WH. Ionizing radiation activates the Nrf2 antioxidant response. Cancer Res. 2010 Nov 1;70(21):8886–95. doi:10.1158/0008-5472.CAN-10-0171 PubMed PMID: 20940400; PubMed Central PMCID: PMC2970706.
42. Jayakumar S, Kunwar A, Sandur SK, Pandey BN, Chaubey RC. Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: role of reactive oxygen species, GSH and Nrf2 in radiosensitivity. Biochim Biophys Acta. 2014 Jan;1840(1):485–94. doi:10.1016/j.bbagen.2013.10.006 PubMed PMID: 24121106.
43. Matsuoka Y, Yoshida R, Kawahara K, Sakata J, Arita H, Nkashima H, Takahashi N, Hirayama M, Nagata M, Hirosue A, Kuwahara Y, Fukumoto M, Toya R, Murakami R, Nakayama H. The antioxidative stress regulator Nrf2 potentiates radioresistance of oral squamous cell carcinoma accompanied with metabolic modulation. Laboratory Investigation. 2022 Aug 1;102(8):896–907. doi:10.1038/s41374-022-00776-w PubMed PMID: 35414650.
44. Feng L, Zhao K, Sun L, Yin X, Zhang J, Liu C, Li B. SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis. Journal of Translational Medicine. 2021 Aug 26;19(1):367. doi:10.1186/s12967-021-03042-7.
45. Wannouss M, Golyshev GG, Goltsov AN. Classification of cancer cell lines on their radiosensitivity by machine learning. Annals of Biostatistics & Biometric Applications. 2023;5(2):2–5.
46. Wannouss M, Shemel VD, Golyshev GG, Goltsov AN. Method for determining radioresistance of cancer cell lines based on cluster analysis of clonogenic cell survival data. Medical Physics (Moscow). 2024;(1):18–35.
47. Lee S, Lim MJ, Kim MH, Yu CH, Yun YS, Ahn J, Song JY. An effective strategy for increasing the radiosensitivity of Human lung Cancer cells by blocking Nrf2-dependent antioxidant responses. Free Radic Biol Med. 2012 Aug 15;53(4):807–16. doi:10.1016/j.freeradbiomed.2012.05.038 PubMed PMID: 22684019.
48. Xue M, Momiji H, Rabbani N, Barker G, Bretschneider T, Shmygol A, Rand DA, Thornalley PJ. Frequency Modulated Translocational Oscillations of Nrf2 Mediate the Antioxidant Response Element Cytoprotective Transcriptional Response. Antioxid Redox Signal. 2015 Sep 1;23(7):613–29. doi:10.1089/ars.2014.5962 PubMed PMID: 25178584; PubMed Central PMCID: PMC4556091.
49. Trachootham D, Lu W, Ogasawara MA, Nilsa RDV, Huang P. Redox regulation of cell survival. Antioxid Redox Signal. 2008 Aug;10(8):1343–74. doi:10.1089/ars.2007.1957 PubMed PMID: 18522489; PubMed Central PMCID: PMC2932530.
50. Ribeiro B. Glutathione: the master antioxidant. Ozone therapy global journal. 2023;13(1):175–97.
51. Sideri S, Petragnano F, Maggio R, Petrungaro S, Catizone A, Gesualdi L, De Martino V, Battafarano G, Del Fattore A, Liguoro D, De Cesaris P, Filippini A, Marampon F, Riccioli A. Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications. Cancers (Basel). 2022 Nov 9;14(22):5504. doi:10.3390/cancers14225504 PubMed PMID: 36428597; PubMed Central PMCID: PMC9688510.
52. Jeong Y, Hoang NT, Lovejoy A, Stehr H, Newman AM, Gentles AJ, Kong W, Truong D, Martin S, Chaudhuri A, Heiser D, Zhou L, Say C, Carter JN, Hiniker SM, Loo BW, West RB, Beachy P, Alizadeh AA, Diehn M. Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer Discov. 2017 Jan;7(1):86–101. doi:10.1158/2159-8290.CD-16-0127 PubMed PMID: 27663899; PubMed Central PMCID: PMC5222718.
53. Fabrizio FP, Sparaneo A, Trombetta D, Muscarella LA. Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs. Oxid Med Cell Longev. 2018;2018:2492063. doi:10.1155/2018/2492063 PubMed PMID: 29643973; PubMed Central PMCID: PMC5872633.
54. Sparaneo A, Torrisi F, D’Angeli F, Giurdanella G, Bravaccini S, Muscarella LA, Fabrizio FP. Decoding the NRF2–NOTCH Crosstalk in Lung Cancer—An Update. Antioxidants (Basel). 2025 May 29;14(6):657. doi:10.3390/antiox14060657 PubMed PMID: 40563292; PubMed Central PMCID: PMC12190023.
55. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S. Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer. PLOS Medicine. 2006 Oct 3;3(10):e420. doi:10.1371/journal.pmed.0030420.
56. Konstantinopoulos PA, Spentzos D, Fountzilas E, Francoeur N, Sanisetty S, Grammatikos AP, Hecht JL, Cannistra SA. Keap1 Mutations and Nrf2 Pathway Activation in Epithelial Ovarian Cancer. Cancer Research. 2011 Jul 28;71(15):5081–9. doi:10.1158/0008-5472.CAN-10-4668.
57. Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, Wu H, Bova GS, Biswal S. Molecular cancer therapeutics. 2010 Feb 2;9(2):336. doi:10.1158/1535-7163.MCT-09-0589 PubMed PMID: 20124447.
58. Yoo NJ, Kim HR, Kim YR, An CH, Lee SH. Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology. 2012 May;60(6):943–52. doi:10.1111/j.1365-2559.2012.04178.x PubMed PMID: 22348534.
59. Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R, Anema J, Craig D, Carpten J, Teh BT, Furge KA. CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Research. 2013 Apr;73(7):2044–51. doi:10.1158/0008-5472.CAN-12-3227 PubMed PMID: 23365135.
60. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, Zhang DD. High Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer. Cancer Research. 2010 Jun 30;70(13):5486–96. doi:10.1158/0008-5472.CAN-10-0713.
61. DeBlasi JM, Falzone A, Caldwell S, Prieto-Farigua N, Prigge JR, Schmidt EE, Chio IIC, Karreth FA, DeNicola GM. Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression. Cancer Res. 2023 Jun 15;83(12):1953–67. doi:10.1158/0008-5472.CAN-22-3848 PubMed PMID: 37062029; PubMed Central PMCID: PMC10267679.
62. Khalil HS, Langdon SP, Goltsov A, Soininen T, Harrison DJ, Bown J, Deeni YY. A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells. Oncotarget. 2016 Oct. doi:10.18632/oncotarget.12425.
63. Tao S, Wang S, Moghaddam SJ, Ooi A, Chapman E, Wong PK, Zhang DD. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Research. 2014 Dec;74(24):7430–41. doi:10.1158/0008-5472.CAN-14-1439 PubMed PMID: 25339352; PubMed Central PMCID: PMC4268230.
64. Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD. Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response. Molecular Cell. 2009 Jun 26;34(6):663–73. doi:10.1016/j.molcel.2009.04.029 PubMed PMID: 19560419.
65. Copple IM. The Keap1-Nrf2 cell defense pathway–a promising therapeutic target? Advances in Pharmacology (San Diego, Calif). 2012;63:43–79. doi:10.1016/B978-0-12-398339-8.00002-1 PubMed PMID: 22776639.
66. Barbano R, Muscarella LA, Pasculli B, Valori VM, Fontana A, Coco M, la Torre A, Balsamo T, Poeta ML, Marangi GF, Maiello E, Castelvetere M, Pellegrini F, Murgo R, Fazio VM, Parrella P. Aberrant Keap1 methylation in breast cancer and association with clinicopathological features. Epigenetics. 2013 Jan 1;8(1):105–12. doi:10.4161/epi.23319 PubMed PMID: 23249627; PubMed Central PMCID: PMC3549873.
67. Muscarella LA, Barbano R, D’Angelo V, Copetti M, Coco M, Balsamo T, la Torre A, Notarangelo A, Troiano M, Parisi S, Icolaro N, Catapano D, Valori VM, Pellegrini F, Merla G, Carella M, Fazio VM, Parrella P. Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient’s outcome. Epigenetics. 2011 Mar;6(3):317–25. doi:10.4161/epi.6.3.14408 PubMed PMID: 21173573; PubMed Central PMCID: PMC3092680.
68. Darnell JE. Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002 Oct;2(10):740–9. doi:10.1038/nrc906
69. Bushweller JH. Targeting transcription factors in cancer ‒ from undruggable to reality. Nat Rev Cancer. 2019 Nov;19(11):611–24. doi:10.1038/s41568-019-0196-7 PubMed PMID: 31511663; PubMed Central PMCID: PMC8820243.
70. Galeaz C, Totis C, Bisio A. Radiation Resistance: A Matter of Transcription Factors. Front Oncol. 2021;11:662840. doi:10.3389/fonc.2021.662840 PubMed PMID: 34141616; PubMed Central PMCID: PMC8204019.
71. Zhou S, Ye W, Shao Q, Zhang M, Liang J. Nrf2 is a potential therapeutic target in radioresistance in human cancer. Critical Reviews in Oncology/Hematology. 2013 Dec;88(3):706–15. doi:10.1016/j.critrevonc.2013.09.001 PubMed PMID: 24126138.
72. Paramasivan P, Kankia IH, Langdon SP, Deeni YY. Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies. Cancer Drug Resistance. 2019 Sep 19;2(3):490–515. doi:10.20517/cdr.2019.57.
73. Goloborodko EV, Kretov AS, Makarov DYu. Non-Drug Methods of Increasing the Radioresistance (Literature Review). MEDICAL RADIOLOGY AND RADIATION SAFETY. 2026;71(3):30–3. doi:10.33266/1024-6177-2026-71-3-30-33.
74. Telkoparan-Akillilar P, Panieri E, Cevik D, Suzen S, Saso L. Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer. Molecules. 2021 Mar 5;26(5):1417. doi:10.3390/molecules26051417 PubMed PMID: 33808001; PubMed Central PMCID: PMC7961421.
75. Pouremamali F, Pouremamali A, Dadashpour M, Soozangar N, Jeddi F. An update of Nrf2 activators and inhibitors in cancer prevention/promotion. Cell Communication and Signaling. 2022 Dec;20(1):100. doi:10.1186/s12964-022-00906-3.
76. El-Naggar AM, Somasekharan SP, Wang Y, Cheng H, Negri GL, Pan M, Wang XQ, Delaidelli A, Rafn B, Cran J, Zhang F, Zhang H, Colborne S, Gleave M, Mandinova A, Kedersha N, Hughes CS, Surdez D, Delattre O, Wang Y, Huntsman DG, Morin GB, Sorensen PH. Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis. EMBO Rep. 2019 Dec 5;20(12):e48375. doi:10.15252/embr.201948375 PubMed PMID: 31668005; PubMed Central PMCID: PMC6893361.
PDF (RUS) Full-text article (in Russian)
Conflict of interest.The authors declare no conflict of interest.
Financing. This work was supported by the Ministry of Science and Higher Education of the Russian Federation (grant No. FGFZ-2026-0007).
Contribution. Article was prepared with equal participation of the authors.
Article received: 20.04.2026. Accepted for publication: 25.05.2026.
Medical Radiology and Radiation Safety. 2026. Vol. 71. № 5
DOI:10.33266/1024-6177-2026-71-5-40-44
A.K. Chigasova1, 2, 3, A.A. Osipov2, M.A. Ignatov1, 2, Yu.A. Fedotov1, 2, V.O. Saburov4, N.Yu. Vorobyova1, 2, A.N. Osipov1, 2
COMPARATIVE STUDIES OF CHANGES IN THE NUMBER OF DNA REPAIR PROTEIN FOCI IN HUMAN MESENCHYMAL STROMAL CELLS IRRADIATED WITH 150 MEV PROTONS OR GAMMA RADIATION
1 A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
2 N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia
3 Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia
4 A.F. Tsyb Medical Radiological Research Center, Obninsk, Russia
Contact person: A.N. Osipov, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
Purpose: Comparative analysis of dose dependences and kinetics of post-radiation changes in the number of DNA repair protein foci (γH2AX and pATM) in human mesenchymal stromal cells (MSCs) exposed to 150 MeV protons or cobalt-60 gamma radiation.
Material and methods: A primary culture of human MSCs obtained from the BioloT LLC collection (Russia) were used in the study. Cells were irradiated at the A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center of Radiology of the Russian Ministry of Health, using the Prometheus proton therapy complex (FTC LPI, Russia) with a 150 MeV proton beam before front of Bragg peak and a ROKUS-AM gamma-therapy unit (cobalt-60). Immunocytochemical staining with antibodies to γH2AX and pATM, respectively, was used to quantify γH2AX and pATM foci.
Results: It was shown that in the case of exposure to gamma radiation, the quantitative yield of foci per unit absorbed dose was 18.56 ± 2.64 and 12.58 ± 1.52 foci / Gy for γH2AX and pATM proteins, respectively. The quantitative yield of foci per unit absorbed dose after exposure to 150 MeV protons was 19.83 ± 2.07 and 10.79 ± 1.51 foci / Gy for γH2AX and pATM proteins, respectively. The studies did not reveal statistically significant differences between the kinetics of post-radiation changes in the number of γH2AX and pATM foci in MSCs irradiated at a dose of 0.5 Gy with 150 MeV protons or cobalt-60 gamma radiation.
Conclusion: A comparative analysis of the dose dependences and kinetics of post-radiation changes in the number of foci of the DNA repair proteins γH2AX and pATM in human MSCs exposed to 150 MeV protons before front of Bragg peak and cobalt-60 gamma radiation revealed no statistically significant differences between the effects of these types of radiation. The obtained results indicate that the RBE of 150 MeV proton radiation before front of Bragg peak relative to cobalt-60 gamma radiation for human MSCs is ~1.0. Immunocytochemical analysis of DNA repair protein foci appears to be very promising for studying the specific cellular response to the DNA-damaging effects of ionizing radiation with different physical characteristics and for biological microdosimetry.
Keywords: protons, γH2AX, gamma-radiation, рATM, DNA damage, DNA repair, mesenchymal stromal cells
For citation: Chigasova AK, Osipov AA, Ignatov MA, Fedotov YuA, Saburov VO, Vorobyova NYu, Osipov AN. Comparative Studies of Changes in the Number of Dna Repair Protein Foci in Human Mesenchymal Stromal Cells Irradiated with 150 Mev Protons or Gamma Radiation. Medical Radiology and Radiation Safety. 2026;71(5):40–44. DOI:10.33266/1024-6177-2026-71-5-40-44
References
1. Kennedy A.R. Biological Effects of Space Radiation and Development of Effective Countermeasures. Life Sci Space Res (Amst). 2014;1:10-43. Doi: 10.1016/j.lssr.2014.02.004.
2. Li Z., Jella K.K., Jaafar L., Li S., Park S., Story M.D., et al. Exposure to Galactic Cosmic Radiation Compromises DNA Repair and Increases the Potential for Oncogenic Chromosomal Rearrangement in Bronchial Epithelial Cells. Sci Rep. 2018;8;1:11038. Doi: 10.1038/s41598-018-29350-5.
3. Mostl C., Amerstorfer T., Palmerio E., Isavnin A., Farrugia C.J., Lowder C., et al. Forward Modeling of Coronal Mass Ejection Flux Ropes in the Inner Heliosphere with 3DCORE. Space Weather. 2018;16;3:216-29. Doi: 10.1002/2017SW001735.
4. Shea M.A., Smart D.F. A Summary of Major Solar Proton Events. Solar Physics. 1990;127;2:297-320. Doi: 10.1007/bf00152170.
5. Vitti E.T., Parsons J.L. The Radiobiological Effects of Proton Beam Therapy: Impact on DNA Damage and Repair. Cancers. 2019;11;7. Doi: 10.3390/cancers11070946.
6. Bianco P., Robey P.G., Simmons P.J. Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays. Cell Stem Cell. 2008;2;4:313-9. Doi: 10.1016/j.stem.2008.03.002.
7. Hematti P. Mesenchymal Stromal Cells and Fibroblasts: a Case of Mistaken Identity? Cytotherapy. 2012;14;5:516-21. Doi: 10.3109/14653249.2012.677822.
8. Zuk P.A., Zhu M., Mizuno H., Huang J., Futrell J.W., Katz A.J., et al. Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies. Tissue Eng. 2001;7;2:211-28. Doi: 10.1089/107632701300062859.
9. Mladenov E., Magin S., Soni A., Iliakis G. DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy. Frontiers in Oncology. 2013 May 10;3:113. Doi: 10.3389/fonc.2013.00113.
10. Penninckx S., Pariset E., Cekanaviciute E., Costes S.V. Quantification of Radiation-Induced DNA Double Strand Break Repair Foci to Evaluate and Predict Biological Responses to Ionizing Radiation. NAR Cancer. 2021;3;4:zcab046. Doi: 10.1093/narcan/zcab046.
11. Belyaev I.Y. Radiation-Induced DNA Repair Foci: Spatio-Temporal Aspects of Formation, Application for Assessment of Radiosensitivity and Biological Dosimetry. Mutat Res. 2010;704;1-3:132-41. Doi: 10.1016/j.mrrev.2010.01.011.
12. Осипов А.А., Чигасова А.К., Яшкина Е.И., Игнатов М.А., Воробьева Н.Ю., Осипов А.Н. Связь между клеточным старением и изменением количества и размера фокусов фосфорилированного гистона H2ax в облученных фибробластах человека // Медицинская радиология и радиационная безопасность. 2024. Т.69. №3. С. 13-18 [Osipov A.A., Chigasova A.K., Yashkina Ye.I., Ignatov M.A., Vorob’yeva N.YU., Osipov A.N. The Relationship between Cellular Senescence and Changes in the Number and Size of Phosphorylated Histone H2ax Foci in Irradiated Human Fibroblasts. Meditsinskaya Radiologiya i Radiatsionnaya Bezopasnost’ = Medical Radiology and Radiation Safety. 2024;69;3:13-18 (In Russ.)]. Doi: 10.33266/1024-6177-2024-69-3-13-18.
13. Чигасова А.К., Пустовалова М.В., Осипов А.А., Корнева С.А., Еремин П.С., Яшкина Е.И. и др. Пострадиационные изменения количества фокусов фосфорилированных белков H2ax и Atm в мезенхимальных стволовых клетках человека, облученных рентгеновским излучением в малых дозах // Медицинская радиология и радиационная безопасность. 2024. Т.69. №1. С. 15-19 [Chigasova A.K., Pustovalova M.V., Osipov A.A., Korneva S.A., Yeremin P.S., Yashkina Ye.I., et al. Post-Radiation Changes in the Number of Foci of Phosphorylated Proteins H2ax and Atm in Human Mesenchymal Stem Cells Irradiated with Low Doses of X-Ray Radiation. Meditsinskaya Radiologiya i Radiatsionnaya Bezopasnost’ = Medical Radiology and Radiation Safety. 2024;69;1:15-19 (In Russ.)]. Doi: 10.33266/1024-6177-2024-69-1-15-19.
14. Jakl L., Markova E., Kolarikova L., Belyaev I. Biodosimetry of Low Dose Ionizing Radiation Using DNA Repair Foci in Human Lymphocytes. Genes (Basel). 2020;11;1. Doi: 10.3390/genes11010058.
15. Falaschi A., Chiaramonte A., Testi S., Scarpato R. Dual Immunofluorescence of gammaH2AX and 53BP1 in Human Peripheral Lymphocytes. J Vis Exp. 2023;197. Doi: 10.3791/65472.
16. Kocher S., Volquardsen J., Perugachi Heinsohn A., Petersen C., Roggenbuck D., Rothkamm K., et al. Fully Automated Counting of DNA Damage Foci in Tumor Cell Culture: a Matter of Cell Separation. DNA Repair (Amst). 2021;102:103100. Doi: 10.1016/j.dnarep.2021.103100.
17. Slonina D., Kowalczyk A., Janecka-Widla A., Kabat D., Szatkowski W., Biesaga B. Low-Dose Hypersensitive Response for Residual pATM and gammaH2AX Foci in Normal Fibroblasts of Cancer Patients. Int J Radiat Oncol Biol Phys. 2018;100;3:756-66. Doi: 10.1016/j.ijrobp.2017.10.054.
18. Ulyanenko S., Pustovalova M., Koryakin S., Beketov E., Lychagin A., Ulyanenko L., et al. Formation of γH2AX and pATM Foci in Human Mesenchymal Stem Cells Exposed to Low Dose-Rate Gamma-Radiation. International Journal of Molecular Sciences. 2019;20;11. Doi: 10.3390/ijms20112645.
19. 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;3:254-63. Doi: 10.1080/09553002.2024.2445581.
20. Корнева С.А., Чигасова А.К., Осипов А.А., Игнатов М.А., Воробьева Н.Ю., Сабуров В.О. и др. Пострадиационные изменения количества фокусов белков γH2ax и pАtm в мезенхимальных стволовых клетках человека, облученных нейтронами с энергией 14,1 МэВ // Медицинская радиология и радиационная безопасность. 2025. Т.70. №3. С. 11-15 [Korneva S.A., Chigasova A.K., Osipov A.A., Ignatov M.A., Vorob’yeva N.YU., Saburov V.O., et al. Post-Radiation Changes in the Number of γH2ax and pАtm Protein Foci in Human Mesenchymal Stem Cells Irradiated with 14.1 MeV Neutrons. Meditsinskaya Radiologiya i Radiatsionnaya Bezopasnost’ = Medical Radiology and Radiation Safety. 2025;70;3:11-15 ( In Russ.)]. Doi: 10.33266/1024-6177-2025-70-3-11-15.
21. Иванов А.А., Бычкова Т.М., Никитенко О.В., Ушаков И.Б. Радиобиологические эффекты протонов // Медицинская радиология и радиационная безопасность. 2019. Т.64. №3. С. 19-31 [Ivanov A.A., Bychkova T.M., Nikitenko O.V., Ushakov I.B. Radiobiological Proton Effects. Meditsinskaya Radiologiya i Radiatsionnaya Bezopasnost’ = Medical Radiology and Radiation Safety. 2019;64;3:19-31 (In Russ.)]. Doi: 10.12737/article_5cf2306a3b26d6.36140627.
PDF (RUS) Full-text article (in Russian)
Conflict of interest.The authors declare no conflict of interest.
Financing. The research was carried out within the framework of the state task of the Ministry of Science and Higher Education of the Russian Federation (No. 1024122500008-3, code FFZE-2025-0030).
Contribution. Article was prepared with equal participation of the authors.
Article received: 20.04.2026. Accepted for publication: 25.05.2026.