In-vitro and in-vivo models for the identification and validation of radioprotectors and radiosensitizers

Debasish Mohapatra# Amlan Priyadarshee Mohapatra# Anjan Kumar Sahoo Shantibhusan Senapati   

Open Access   

Published:  Nov 10, 2022

DOI: 10.7324/JABB.2023.110208

Radiation therapy has emerged as a mainstay therapeutic approach for cancer therapy. Radiation therapy includes beams of intense energy that destroy cancer cells by targeting their genetic material. Radiation treatment is a localized therapy that can be used to shrink the tumor for which it will be eligible for surgery. Chemoradiation combination is often used to inhibit the rapid proliferation and metastasis of cancer. Although radiation therapy is an important therapeutic modality for cancer, its adverse effect on normal cells and unwanted side effects cannot be ignored. Therefore, with the increase in cancer prevalence, the clinical management of radiation therapy has become a major challenge in cancer therapy. The challenges in radiation therapy can be addressed by identifying novel radiation modifiers that can potentiate the low dose of radiation on cancer, protect normal cells from radiation, and suppress radiation-induced side effects. The search for radiation modifiers needs a suitable model system through which potential radiosensitizers and radioprotectors can be screened and validated to be used in the radiation field. Keeping the importance of a suitable model in the clinical management of radiation therapy, we have discussed different models in this review that can be used to screen radiation modifiers.

Keyword:     Cancer Radiation Radioprotectors Radiosensitizer Radiation modifiers Zebrafish organoid model system


Mohapatra D, Mohapatra AP, Sahoo AK, Senapati S. In-vitro and in-vivo models for the identification and validation of radioprotectors and radiosensitizers. J App Biol Biotech, 2022.

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license.

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1. Baskar R, Dai J, Wenlong N, Yeo R, Yeoh KW. Biological response of cancer cells to radiation treatment. Front Mol Biosci 2014;1:24.

2. Biau J, Chautard E, Verrelle P, Dutreix M. Altering DNA repair to improve radiation therapy: Specific and multiple pathway targeting. Front Oncol 2019;9:1009.

3. Deng L, Liang H, Fu S, Weichselbaum RR, Fu YX. From dna damage to nucleic acid sensing: A strategy to enhance radiation therapy. Clin Cancer Res 2016;22:20-5.

4. Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: A review. Plast Reconstr Surg 2014;133:49e-56.

5. Fan H, Demirci U, Chen P. Emerging organoid models: Leaping forward in cancer research. J Hematol Oncol 2019;12:142.

6. Pasch CA, Favreau PF, Yueh AE, Babiarz CP, Gillette AA, Sharick JT, et al. Patient-derived cancer organoid cultures to predict sensitivity to chemotherapy and radiation. Clin Cancer Res 2019;25:5376-87.

7. Hubert CG, Rivera M, Spangler LC, Wu Q, Mack SC, Prager BC, et al. A Three-dimensional organoid culture system derived from human glioblastomas recapitulates the hypoxic gradients and cancer stem cell heterogeneity of tumors found in vivo. Cancer Res 2016;76:2465-77.

8. Linkous A, Balamatsias D, Snuderl M, Edwards L, Miyaguchi K, Milner T, et al. Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep 2019;26:3203-11.e5.

9. Park M, Kwon J, Youk H, Shin US, Han YH, Kim Y. Valproic acid protects intestinal organoids against radiation via NOTCH signaling. Cell Biol Int 2021;45:1523-32.

10. Cosper PF, Abel L, Lee YS, Paz C, Kaushik S, Nickel KP, et al. Patient derived models to study head and neck cancer radiation response. Cancers (Basel) 2020;12:419.

11. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461:1071-8.

12. Pollard JM, Gatti RA. Clinical radiation sensitivity with DNA repair disorders: An overview. Int J Radiat Oncol Biol Phys 2009;74:1323-31.

13. McKenna WG, Muschel RJ, Gupta AK, Hahn SM, Bernhard EJ. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 2003;22:5866-75.

14. Toulany M, Rodemann HP. Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation. Semin Cancer Biol 2015;35:180-90.

15. Lacerda L, Reddy JP, Liu D, Larson R, Li L, Masuda H, et al. Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl Med 2014;3:849-56.

16. Chen YA, Shih HW, Lin YC, Hsu HY, Wu TF, Tsai CH, et al. Simvastatin sensitizes radioresistant prostate cancer cells by compromising dna double-strand break repair. Front Pharmacol 2018;9:600.

17. Mohapatra D, Das B, Suresh V, Parida D, Minz AP, Nayak U, et al. Fluvastatin sensitizes pancreatic cancer cells toward radiation therapy and suppresses radiation- and/or TGF-β-induced tumor-associated fibrosis. Lab Invest 2021;102:298-311.

18. Kriegs M, Kasten-Pisula U, Rieckmann T, Holst K, Saker J, Dahm-Daphi J, et al. The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. DNA Repair (Amst) 2010;9:889-97.

19. Myllynen L, Rieckmann T, Dahm-Daphi J, Kasten-Pisula U, Petersen C, Dikomey E, et al. In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status. Radiother Oncol 2011;101:147-51.

20. Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R, Kufe D. Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest 1991;88:691-5.

21. Yamagishi N, Miyakoshi J, Takebe H. Enhanced radiosensitivity by inhibition of nuclear factor kappa B activation in human malignant glioma cells. Int J Radiat Biol 1997;72:157-62.

22. Veuger SJ, Hunter JE, Durkacz BW. Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance. Oncogene 2009;28:832-42.

23. Yang S, Han G, Chen Q, Yu L, Wang P, Zhang Q, et al. Au-Pt Nanoparticle formulation as a radiosensitizer for radiotherapy with dual effects. Int J Nanomed 2021;16:239-48.

24. Narayan RS, Gasol A, Slangen PL, Cornelissen FM, Lagerweij T, Veldman H, et al. Identification of MEK162 as a radiosensitizer for the treatment of glioblastoma. Mol Cancer Ther 2018;17:347-54.

25. Mattiazzi M, Petrovi? U, Križaj I. Yeast as a model eukaryote in toxinology: A functional genomics approach to studying the molecular basis of action of pharmacologically active molecules. Toxicon 2012;60:558-71.

26. Botstein D, Chervitz SA, Cherry JM. Yeast as a model organism. Science 1997;277:1259-60.

27. Huang RX, Zhou PK. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther 2020;5:60.

28. Vaidya PJ, Pasupathy K. Radioprotective action of caffeine: Use of saccharomyces cerevisiae as a test system. Indian J Exp Biol 2001;39:1254-7. 29. Song S, McCann KE, Brown JM. Radiosensitization of yeast cells by inhibition of histone h4 acetylation. Radiat Res 2008;170:618-27.

30. Pasupathy K, Nair CK, Kagiya TV. Effect of a hypoxic radiosensitizer, AK 2123 (Sanazole), on yeast Saccharomyces cerevisiae. J Radiat Res 2001;42:217-27.

31. Dolling JA, Boreham DR, Brown DL, Raaphorst GP, Mitchel RE. Cisplatin-modification of DNA repair and ionizing radiation lethality in yeast, Saccharomyces cerevisiae. Mutat Res 1999;433:127-36.

32. Nemavarkar P, Chourasia BK, Pasupathy K. Evaluation of radioprotective action of compounds using Saccharomyces cerevisiae. J Environ Pathol Toxicol Oncol 2004;23:145-51.

33. Kishi S, Uchiyama J, Baughman AM, Goto T, Lin MC, Tsai SB. The zebrafish as a vertebrate model of functional aging and very gradual senescence. Exp Gerontol 2003;38:777-86.

34. Jaafar L, Podolsky RH, Dynan WS. Long-term effects of ionizing radiation on gene expression in a zebrafish model. PLoS One 2013;8:e69445.

35. Raldúa D, Piña B. In vivo zebrafish assays for analyzing drug toxicity. Expert Opin Drug Metab Toxicol 2014;10:685-97.

36. Fior R, Póvoa V, Mendes RV, Carvalho T, Gomes A, Figueiredo N, et al. Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts. Proc Natl Acad Sci U S A 2017;114:E8234-43.

37. Geiger GA, Parker SE, Beothy AP, Tucker JA, Mullins MC, Kao GD. Zebrafish as a "biosensor"? Effects of ionizing radiation and amifostine on embryonic viability and development. Cancer Res 2006;66:8172-81.

38. McAleer MF, Davidson C, Davidson WR, Yentzer B, Farber SA, Rodeck U, et al. Novel use of zebrafish as a vertebrate model to screen radiation protectors and sensitizers. Int J Radiat Oncol Biol Phys 2005;61:10-3.

39. McAleer MF, Duffy KT, Davidson WR, Kari G, Dicker AP, Rodeck U, et al. Antisense inhibition of cyclin D1 expression is equivalent to flavopiridol for radiosensitization of zebrafish embryos. Int J Radiat Oncol Biol Phys 2006;66:546-51.

40. Barriuso J, Nagaraju R, Hurlstone A. Zebrafish: A new companion for translational research in oncology. Clin Cancer Res 2015;21:969-75.

41. Lally BE, Geiger GA, Kridel S, Arcury-Quandt AE, Robbins ME, Kock ND, et al. Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library. Cancer Res 2007;67:8791-9.

42. Geiger GA, Fu W, Kao GD. Temozolomide-mediated radiosensitization of human glioma cells in a zebrafish embryonic system. Cancer Res 2008;68:3396-404.

43. Gnosa S, Capodanno A, Murthy RV, Jensen LD, Sun XF. AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model. Oncotarget 2016;7:81634-44.

44. Daroczi B, Kari G, McAleer MF, Wolf JC, Rodeck U, Dicker AP. In vivo radioprotection by the fullerene nanoparticle DF-1 as assessed in a zebrafish model. Clin Cancer Res 2006;12:7086-91.

45. Adenan MN, Yazan LS, Christianus A, Md Hashim NF, Mohd Noor S, Shamsudin S, et al. Radioprotective effects of kelulut honey in zebrafish model. Molecules 2021;26:1557.

46. Liu G, Zeng Y, Lv T, Mao T, Wei Y, Jia S, et al. High-throughput preparation of radioprotective polymers via Hantzsch's reaction for in vivo X-ray damage determination. Nat Commun 2020;11:6214.

47. Sharpless NE, Depinho RA. The mighty mouse: Genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 2006;5:741-54.

48. Moding EJ, Castle KD, Perez BA, Oh P, Min HD, Norris H, et al. Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy. Sci Transl Med 2015;7:278ra34.

49. Blattmann C, Thiemann M, Stenzinger A, Christmann A, Roth E, Ehemann V, et al. Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model. Strahlenther Onkol 2013;189:957-66.

50. Doiron A, Yapp DT, Olivares M, Zhu JX, Lehnert S. Tumor radiosensitization by sustained intratumoral release of bromodeoxyuridine. Cancer Res 1999;59:3677-81.

51. Liu P, Jin H, Guo Z, Ma J, Zhao J, Li D, et al. Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma. Int J Nanomed 2016;11:5003-14.

52. Kunwar A, Adhikary B, Jayakumar S, Barik A, Chattopadhyay S, Raghukumar S, et al. Melanin, a promising radioprotector: Mechanisms of actions in a mice model. Toxicol Appl Pharmacol 2012;264:202-11.

53. Feng L, Li J, Qin L, Guo D, Ding H, Deng D. Radioprotective effect of lactoferrin in mice exposed to sublethal X-ray irradiation. Exp Ther Med 2018;16:3143-8.

54. Nair GG, Nair CK. Radioprotective effects of gallic acid in mice. Biomed Res Int 2013;2013:953079.

55. Lu X, Nurmemet D, Bolduc DL, Elliott TB, Kiang JG. Radioprotective effects of oral 17-dimethylaminoethylamino-17- demethoxygeldanamycin in mice: Bone marrow and small intestine. Cell Biosci 2013;3:36.

56. Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, et al. Animal models for medical countermeasures to radiation exposure. Radiat Res 2010;173:557-78.

57. Castle KD, Chen M, Wisdom AJ, Kirsch DG. Genetically engineered mouse models for studying radiation biology. Transl Cancer Res 2017;6:S900-13.

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