Radioprotection in the 21st Century

In nature, there are bacteria and eukaryotic multicellular organisms (insects, arthropods) that have extraordinary, nevertheless still poorly understood radiation resistance. Knowledge of its mechanisms can significantly increase the effectiveness of radioprotectors and can lead to fundamental discoveries for the radioprotection in humans.
Relevance. The growing threat of nuclear war and nuclear accidents requires updating and deepening the knowledge of the occurrence of radiation resistance in nature and the development of pharmaceutical means for human radiation protection.
The purpose of the study is to summarize the ideas available in the scientific literature about the mechanisms of increased radiation resistance of some living organisms and about modern radioprotectors.
The source base of the study. Scientific publications available through the biomedical research database PubMed. Research method. Analytical.
Discussion. The reasons for the high radioresistance of the bacterium Deinococcus radiodurans and scorpions of the genus Androctonus are considered. For D. radiodurans, the radioresistance is based on the ability to protect its proteome, and not the genome, as previously thought. The resistance of bacterial cells to radiation is regulated by manganese antioxidants. With this ability, D. radiodurans can repair up to 500 breaks, while E. coli can repair two or three DNA breaks at once. The new bioconcept can be expressed as “Primacy of the proteome over the genome”. The principle of the radioresistance of scorpions is less clear. It is known that the main role is played by the hemolymph cells the anulocytes (“hémocytes annelés”), and hemocyanin molecules present freelely in the hemolymph. The paper further describes general therapeutic approaches to the development of new radioprotective agents. Radioprotectors are supposed to prevent/inhibit the formation of free radicals caused by radiation (most of which are formed during radiolysis of water), thereby inhibiting their reactions with biomolecules reducing the frequency of DNA strand breaks and preventing the occurrence of cellular disorders. The classification of radioprotectors is given, their properties are described in detail.
Conclusions. For the future development of radioprotectors, it is important to recognize the “new” paradigm of radioresistance – the “primacy of the proteome over the genome”. From today's practical point of view, the cytoprotective complexing drug Amifostine can be recommended in radiation protection.

1. Vachon M, Aeberhardt A, Grenot C, Niaussat P, Pierre F. On the radiosensitivity of the Sahara scorpion Androctonus amoreuxi (Aud. and Sav.). C R Hebd Seances Acad Sci. 1963;256:4290–3. French. PMID: 13995671.

2. Goyffon M. Resistance to ionizing radiation. In: Stockmann R, Ythier E.: Scorpions of the World. N.A.P. Editions, Verrières-le-Buisson; 2010. P. 157–63. ISBN 978-2913688117 https://1lib.sk/book/2034275/80fdf1/scorpions-of-the-world.html

3. Huyart N, Calvayrac R, Briand J, Goyffon M, Vuillaume M. Catalatic properties of hemocyanin in helping to account for the scorpion’s radioresistance. Comp Biochem Physiol. 1983;76B:153–9. https://doi.org/10.1016/0305-0491(83)90187-6

4. Anderson A, Nordon H, Cain RF, Parrish G, Duggan D, Anderson A. Studies on a radio-resistant micrococcus. I. Isolation, morphology, cultural characteristics, and resistance to gamma radiation. Food Technol. 1956;10(1):575–7.

5. Huyghe P. Conan the bacterium. Sciences. 1998;38(4):16–9.

6. Daly MJ. A new perspective on radiation resistance based on Deinococcus radiodurans. Nat Rev Microbiol. 2009;7(3):237–45. https://doi.org/10.1038/nrmicro2073

7. Daly MJ, Gaidamakova EK, Matrosova VY, Kiang JG, Fukumoto R, Lee DY, et al. Small-molecule antioxidant proteome-shields in Deinococcus radiodurans. PLoS One. 2010;5(9):e12570. https://doi.org/10.1371/journal.pone.0012570

8. Krisko A, Radman M. Biology of extreme radiation resistance: the way of Deinococcus radiodurans. Cold Spring Harb Perspect Biol. 2013;5(7):a012765. https://doi.org/10.1101/cshperspect.a012765

9. de Toledo Arruda-Neto JD, Righi H, Cabrera Gomez JG, Ferreira da Silva L, Drigo E, da Costa Lemos AC. Radioresistance and radiosensitivity: a biophysical approach on bacterial cells robustness. Theory Biosci. 2023;142:13–28. https://doi.org/10.1007/s12064-022-00382-w

10. Daly MJ. The scientific revolution that unraveled the astonishing DNA repair capacity of the Deinococcaceae: 40 years on. Can J Microbiol. 2023;69(10):369–86. https://doi.org/10.1139/cjm-2023-0059 Erratum in: Can J Microbiol. 2023;69(11):463. https://doi.org/10.1139/cjm-2023-0128

11. Hutchinson F. The molecular basis for radiation effects on cells. Cancer Res. 1966;26(9):2045–52. PMID: 5924966.

12. Daly MJ, Gaidamakova EK, Matrosova VY, Vasilenko A, Zhai M, Venkateswaran A, et al. Accumulation of Mn(II) in Deinococcus radiodurans facilitates gamma-radiation resistance. Science. 2004;306(5698):1025–8. https://doi.org/10.1126/science.1103185

13. Daly MJ, Gaidamakova EK, Matrosova VY, Vasilenko A, Zhai M, Leapman RD, et al. Protein oxidation implicated as the primary determinant of bacterial radioresistance. PLoS Biol. 2007;5(4):e92. https://doi.org/10.1371/journal.pbio.0050092

14. Krisko A, Radman M. Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans. Proc Natl Acad Sci USA. 2010;107(32):14373–7. https://doi.org/10.1073/pnas.1009312107

15. Sharma A, Gaidamakova EK, Grichenko O, Matrosova VY, Hoeke V, Klimenkova P, et al. Across the tree of life, radiation resistance is governed by antioxidant Mn2+, gauged by paramagnetic resonance. Proc Natl Acad Sci USA. 2017;114(44):E9253–60. https://doi.org/10.1073/pnas.1713608114

16. Bruckbauer ST, Minkoff BB, Sussman MR, Cox MM. Proteome Damage Inflicted by Ionizing Radiation: Advancing a Theme in the Research of Miroslav Radman. Cells. 2021;10(4):954. https://doi.org/10.3390/cells10040954

17. Bruce AK. Extraction of the radioresistant factor of Micrococcus radiodurans. Radiat Res. 1964;22:155–64. PMID: 14157356.

18. Setlow JK, Duggan DE. The resistance of micrococcus radiodurans to ultraviolet radiation. I. Ultravioletinduced lesions in the cell's DNA. Biochim Biophys Acta. 1964;87:664–8. https://doi.org/10.1016/0926-6550(64)90284-1

19. Leibowitz PJ, Schwartzberg LS, Bruce AK. The in vivo association of manganese with the chromosome of Micrococcus radiodurans. Photochem Photobiol. 1976;23(1):45–50. https://doi.org/10.1111/j.1751-1097.1976.tb06769.x

20. Brim H, Venkateswaran A, Kostandarithes HM, Fredrickson JK, Daly MJ. Engineering Deinococcus geothermalis for bioremediation of high-temperature radioactive waste environments. Appl Environ Microbiol. 2003;69(8):4575–82. https://doi.org/10.1128/AEM.69.8.4575-4582.2003

21. Daly MJ. Modulating radiation resistance: Insights based on defenses against reactive oxygen species in the radioresistant bacterium Deinococcus radiodurans. Clin Lab Med. 2006;26(2):491–504. https://doi.org/10.1016/j.cll.2006.03.009

22. Daly MJ. A new perspective on radiation resistance based on Deinococcus radiodurans. Nat Rev Microbiol. 2009;7(3):237–45. https://doi.org/10.1038/nrmicro2073

23. Gaidamakova EK, Sharma A, Matrosova VY, Grichenko O, Volpe RP, Tkavc R, et al. Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation. mBio. 2022;13(1):e0339421. https://doi.org/10.1128/mbio.03394-21

24. Horne WH, Volpe RP, Korza G, DePratti S, Conze IH, Shuryak I, et al. Effects of Desiccation and Freezing on Microbial Ionizing Radiation Survivability: Considerations for Mars Sample Return. Astrobiology. 2022;22(11):1337–50. https://doi.org/10.1089/ast.2022.0065

25. Debajyoti Das. Biochemistry, 14th ed., Kolkata, India: Academic Publ. 2010; P. 320–321.

26. Daly MJ, Gaidamakova EK, Matrosova VY, Vasilenko A, Zhai M, Leapman RD, et al. Protein oxidation implicated as the primary determinant of bacterial radioresistance. PLoS Biol. 2007;5(4):e92. https://doi.org/10.1371/journal.pbio.0050092

27. Hood MN, Ayompe E, Holmes-Hampton GP, Korotcov A, Wuddie K, Aschenake Z, et al. Preliminary Promising Findings for Manganese Chloride as a Novel Radiation Countermeasure Against Acute Radiation Syndrome. Mil Med. 2024;189(Suppl 3):598–607. https://doi.org/10.1093/milmed/usae198

28. Tobin GJ, Tobin JK, Gaidamakova EK, Wiggins TJ, Bushnell RV, Lee WM, et al. A novel gamma radiationinactivated sabin-based polio vaccine. PLoS One. 2020;15(1):e0228006. https://doi.org/10.1371/journal.pone.0228006

29. Gupta P, Gayen M, Smith JT, Gaidamakova EK, Matrosova VY, Grichenko O, et al. MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation. PLoS One. 2016;11(8):e0160575. https://doi.org/10.1371/journal.pone.0160575

30. Gaidamakova EK, Myles IA, McDaniel DP, Fowler CJ, Valdez PA, Naik S, et al. Preserving immunogenicity of lethally irradiated viral and bacterial vaccine epitopes using a radio- protective Mn2+-Peptide complex from Deinococcus. Cell Host Microbe. 2012;12(1):117–24. https://doi.org/10.1016/j.chom.2012.05.011

31. Khurana H, Hazari PP, Mishra AK. Radioprotective efficacy of GSH based peptidomimetic complex of manganese against radiation induced damage: DT(GS)2Mn(II). Free Radic Biol Med. 2019;145:161–74. https://doi.org/10.1016/j.freeradbiomed.2019.09.023

32. Goyffon M, Vincent R. 'Radioresistance of Scorpions'. In: Brownell P, Polis G, Eds. Scorpion Biology and Research. New York: Oxford Academic; 2001 (online edn, 31 Oct. 2023). https://doi.org/10.1093/oso/9780195084344.003.0017

33. Stockmann R. Introduction to Scorpion Biology and Ecology. In: Gopalakrishnakone P, Possani L, F. Schwartz E, Rodríguez de la Vega de la Vega R, Eds. Scorpion Venoms. Toxinology, Vol. 4. Dordrecht: Springer; 2015. https://doi.org/10.1007/978-94-007-6404-0_14

34. Huyart N, Calvayrac R, Briand J, Goyffon M, Vuillaume M. Catalatic properties of hemocyanin in helping to account for the scorpion’s radioresistance. Comp Biochem Physiol B. 1983;76(1):153–9. https://doi.org/10.1016/0305-0491(83)90187-6

35. Quéinnec E, Gardès-Albert M, Goyffon M, Ferradini C, Vuillaume M. Antioxidant activity of hemocyanin; a pulse radiolysis study. Biochim Biophys Acta. 1990;1041(2):153–9. https://doi.org/10.1016/0167-4838(90)90059-o

36. Queinnec E, Gardes-Albert M, Ducancel F, Goyffon M, Ferradini C, Vuillaume M. Etude cinétique des propriétés catalytiques de l'hémocyanine de scorpion. Radioprotection. 1991;26(4):637–47. https://doi.org/10.1051/radiopro/1991023

37. Ravindranath MH. The hemocytes of a scorpion Palamnaeus swammerdami. J Morphol. 1974;144(1):1–10. https://doi.org/10.1002/jmor.1051440102

38. Mishra K, Alsbeih G. Appraisal of biochemical classes of radioprotectors: evidence, current status and guidelines for future development. J Biotech. 2017;7(5):292. https://doi.org/10.1007/s13205-017-0925-0

39. Montoro A, Obrador E, Mistry D, Forte G, Bravatà V, Minafra L, et al. Radioprotectors, Radiomitigators, and Radiosensitizers. In: Baatout S. Ed. Radiobiology Textbook. Cham: Springer; 2023. https://doi.org/10.1007/978-3-031-18810-7_11

40. Weiss JF, Landauer MR. Radioprotection by antioxidants. Ann N Y Acad Sci. 2000;899:44–60. PMID: 10863528.

41. Singh VK, Seed TM. The efficacy and safety of amifostine for the acute radiation syndrome. Expert Opin Drug Saf. 2019;18(11):1077–90. https://doi.org/10.1080/14740338.2019.1666104

42. Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist. 2010;15(4):360–71. https://doi.org/10.1634/theoncologist.2009-S104

43. Huang EY, Wang FS, Chen YM, Chen YF, Wang CC, Lin IH, et al. Amifostine alleviates radiationinduced lethal small bowel damage via promotion of 14-3-3σ-mediated nuclear p53 accumulation. Oncotarget. 2014;5(20):9756–69. https://doi.org/10.18632/oncotarget.2386

44. Hofer M, Falk M, Komůrková D, Falková I, Bačíková A, Klejdus B, et al. Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells. J Med Chem. 2016;59(7):3003–17. https://doi.org/10.1021/acs.jmedchem.5b01628

45. Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PLoS One. 2014;9(5):e95968. https://doi.org/10.1371/journal.pone.0095968

46. Patyar RR, Patyar S. Role of drugs in the prevention and amelioration of radiation induced toxic effects. Eur J Pharmacol. 2018;819:207–16. https://doi.org/10.1016/j.ejphar.2017.12.011

47. Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev. 2009;2(5):270–8. https://doi.org/10.4161/oxim.2.5.9498

48. Liu J, Bai R, Liu Y, Zhang X, Kan J, Jin C. Isolation, structural characterization and bioactivities of naturally occurring polysaccharide-polyphenolic conjugates from medicinal plants-A reivew. Int J Biol Macromol. 2018;107(Pt B):2242–50. https://doi.org/10.1016/j.ijbiomac.2017.10.097

49. Liu Z, Lei X, Li X, Cai JM, Gao F, Yang YY. Toll-like receptors and radiation protection. Eur Rev Med Pharmacol Sci. 2018;22(1):31–9. https://doi.org/10.26355/eurrev_201801_14097

50. Hosseinimehr SJ. The protective effects of trace elements against side effects induced by ionizing radiation. Radiat Oncol J. 2015;33(2):66–74. https://doi.org/10.3857/roj.2015.33.2.66

51. Doctrow SR, Lopez A, Schock AM, Duncan NE, Jourdan MM, Olasz EB, A synthetic superoxide dismutase/ catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin. J Invest Dermatol. 2013;133(4):1088–96. https://doi.org/10.1038/jid.2012.410

52. Batinic-Haberle I, Tovmasyan A, Spasojevic I. Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury. Antioxid Redox Signal. 2018;29(16):1691–724. https://doi.org/10.1089/ars.2017.7453

53. Mapuskar KA, Anderson CM, Spitz DR, Batinic-Haberle I, Allen BG, Oberley-Deegan RE. Utilizing Superoxide Dismutase Mimetics to Enhance Radiation Therapy Response While Protecting Normal Tissues. Semin Radiat Oncol. 2019;29(1):72–80. https://doi.org/10.1016/j.semradonc.2018.10.005