Vitamins D and E as radiotherapy adjuncts - literature review of preclinical and clinical evidence
DOI:
https://doi.org/10.12775/JEHS.2026.88.68325Keywords
radiotherapy, radiation, vitamin D, vitamin E, radiosensitivityAbstract
Introduction: Radiotherapy (RT) is the fundamental method in cancer treatment, yet tumor resistance and normal tissue toxicity limit its efficacy. Vitamins D and E may modulate RT outcomes through radiosensitization, antioxidant effects, and immune regulation.
Methods and Materials: We reviewed preclinical and clinical studies from PubMed, ScienceDirect, ResearchGate, and Google Scholar using keywords like “radiotherapy”, ”radiation”, “vitamin D”, “vitamin E” and “radiosensitivity”.
Results: Vitamin D enhances RT response via VDR-mediated DNA damage and reduces toxicity (e.g., mucositis), though hypercalcemia risk requires monitoring. Vitamin E (especially tocotrienols) alleviates mucositis and fibrosis, but excessive doses may compromise RT efficacy by neutralizing tumor-killing ROS.
Conclusions: Vitamins D and E show therapeutic potential in RT but require precise dosing and timing to avoid interference with treatment. Personalized strategies and robust clinical trials are needed to establish evidence-based guidelines for their adjuvant use.
References
1. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10-45. doi:10.3322/caac.21871
2. Martin OA, Martin RF. Cancer Radiotherapy: Understanding the Price of Tumor Eradication. Front Cell Dev Biol. 2020;8:261. Published 2020 Apr 24. doi:10.3389/fcell.2020.00261
3. Krzyszczyk P, Acevedo A, Davidoff EJ, et al. The growing role of precision and personalized medicine for cancer treatment. Technology (Singap World Sci). 2018;6(3–4):79–100. doi:10.1142/S2339547818300020
4. Giulietti A. Laser-driven particle acceleration for radiobiology and radiotherapy. In: Proceedings of SPIE 10239, Medical Applications of Laser-Generated Beams of Particles IV; 2017:1023904. doi:10.1117/12.2270945.
5. Guo Z, Lei L, Zhang Z, Du M, Chen Z. The potential of vascular normalization for sensitization to radiotherapy. Heliyon. 2024;10(12):e32598. Published 2024 Jun 8. doi:10.1016/j.heliyon.2024.e32598
6. Kumari N, Raghavan SC. G-quadruplex DNA structures and their relevance in radioprotection. Biochim Biophys Acta Gen Subj. 2021;1865(5):129857. doi:10.1016/j.bbagen.2021.129857
7. Gong L, Zhang Y, Liu C, Zhang M, Han S. Application of Radiosensitizers in Cancer Radiotherapy [published correction appears in Int J Nanomedicine. 2021 Dec 16;16:8139-8140. doi: 10.2147/IJN.S352169.]. Int J Nanomedicine. 2021;16:1083-1102. Published 2021 Feb 12. doi:10.2147/IJN.S290438
8. Wang H, Mu X, He H, Zhang XD. Cancer Radiosensitizers. Trends Pharmacol Sci. 2018;39(1):24-48. doi:10.1016/j.tips.2017.11.003
9. Conti V, Polcaro G, De Bellis E, et al. Natural Health Products for Anti-Cancer Treatment: Evidence and Controversy. J Pers Med. 2024;14(7):685. Published 2024 Jun 26. doi:10.3390/jpm14070685
10. Kabakov, A.E.; Yakimova, A.O. Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing. Cancers 2021, 13, 1102.
11. Liu, Y.; Zheng, C.; Huang, Y.; He, M.; Xu, W.W.; Li, B. Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm 2021, 2, 315–340.
12. Olivares-Urbano, M.A.; Griñán-Lisón, C.; Marchal, J.A.; Núñez, M.I. CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer. Cells 2020, 9, 1651.
13. Du M, Luo H, Blumberg JB, et al. Dietary Supplement Use among Adult Cancer Survivors in the United States. J Nutr. 2020;150(6):1499-1508. doi:10.1093/jn/nxaa040
14. Song, S., Youn, J., Lee, Y. J., Kang, M., Hyun, T., Song, Y., & Lee, J. E. (2017). Dietary Supplement Use Among Cancer Survivors and the General Population: A Nation-Wide Cross-Sectional Study. BMC Cancer, 17, 891.
15. Reiter RJ, Chuffa LGA, Simão VA, et al. Melatonin and vitamin D as potential synergistic adjuvants for cancer therapy (Review). Int J Oncol. 2024;65:114. doi:10.3892/ijo.2024.5702.
16. Wu X, Hu W, Lu L, et al. Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta Pharm Sin B. 2019;9(2):203–219. doi:10.1016/j.apsb.2018.09.002.
17. Afonso ML, Capelas ML, Pimenta NM, et al. A Systematic Review of Vitamin D Supplementation in Oncology: Chance of Science or Effectiveness? Nutrients. 2025;17(4):634. doi:10.3390/nu17040634.
18. Yu X, Liu B, Zhang N, et al. Immune Response: A Missed Opportunity Between Vitamin D and Radiotherapy. Front Cell Dev Biol. 2021;9:646981. doi:10.3389/fcell.2021.646981.
19. Nuszkiewicz J, Woźniak A, Szewczyk-Golec K. Ionizing Radiation as a Source of Oxidative Stress—The Protective Role of Melatonin and Vitamin D. Int J Mol Sci. 2020;21(16):5804. doi:10.3390/ijms21165804.
20. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317(12):1234-1243.
21. Huang R, Xiang J, Zhou P. Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle. J Exp Clin Cancer Res. 2019;38:493. doi:10.1186/s13046-019-1499-y.
22. Ji MT, Nie J, Nie XF, et al. 1α,25(OH)₂D₃ radiosensitizes cancer cells by activating the NADPH/ROS pathway. Front Pharmacol. 2020;11:945. doi:10.3389/fphar.2020.00945.
23. Chen PT, Hsieh CC, Chen MF. Role of vitamin D₃ in tumor aggressiveness and radiation response for hepatocellular carcinoma. Mol Carcinog. 2022;61(8):787–796. doi:10.1002/mc.23421.
24. Mukai Y, Yamada D, Eguchi H, et al. Vitamin D supplementation is a promising therapy for pancreatic ductal adenocarcinoma in conjunction with current chemoradiation therapy. Ann Surg Oncol. 2018;25(7):1868-1879. doi:10.1245/s10434-018-6431-8.
25. Gao C, Jian C, Wang L, et al. FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy. Int J Pharm. 2025;670:125190. doi:10.1016/j.ijpharm.2025.125190.
26. Langberg M, Rotem C, Fenig E, Koren R, Ravid A. Vitamin D protects keratinocytes from deleterious effects of ionizing radiation. Br J Dermatol. 2009;160(1):151–161. doi:10.1111/j.1365-2133.2008.08797.x.
27. Marampon F, Gravina GL, Festuccia C, et al. Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis. J Endocrinol Invest. 2016;39(4):411–422. doi:10.1007/s40618-015-0381-9.
28. Lin Y, Xia P, Cao F, et al. Protective effects of activated vitamin D receptor on radiation-induced intestinal injury. J Cell Mol Med. 2023;27(1):246–258. doi:10.1111/jcmm.17645.
29. Podgórska E, Drzał A, Matuszak Z, et al. Calcitriol and calcidiol can sensitize melanoma cells to low–LET proton beam irradiation. Int J Mol Sci. 2018;19(8):2236. doi:10.3390/ijms19082236.
30. Wu CT, Huang YC, Chen WC, Chen MF. Effect of 1α,25-dihydroxyvitamin D₃ on the radiation response in prostate cancer: Association with IL-6 signaling. Front Oncol. 2021;11:619365. doi:10.3389/fonc.2021.619365.
31. Yu X, Wang Q, Liu B, Zhang N, Cheng G. Vitamin D enhances radiosensitivity of colorectal cancer by reversing epithelial-mesenchymal transition. Front Cell Dev Biol. 2021;9:684855. doi:10.3389/fcell.2021.684855.
32. Zhang Z, Yu X, Cheng G. Vitamin D sensitizes cervical cancer to radiation-induced apoptosis by inhibiting autophagy through degradation of Ambra1. Cell Death Discov. 2025;11:1. doi:10.1038/s41420-024-02279-7.
33. Trémezaygues L, Seifert M, Vogt T, Tilgen W, Reichrath J. 1,25-Dihydroxyvitamin D3 modulates effects of ionizing radiation on human keratinocytes: In vitro analysis of cell viability/proliferation, DNA damage, and repair. J Steroid Biochem Mol Biol. 2010;121(1-2):324–327. doi:10.1016/j.jsbmb.2010.03.007.
34. Bakr IS, Zaki AM, El-Moslemany R, Elsaka RO. Vitamin D oral gel for prevention of radiation-induced oral mucositis: A randomized clinical trial. Oral Dis. 2021;27(1):1197–1204. doi:10.1111/odi.13650.
35. Anand A, Singh S, Sonkar AA, et al. Expression of vitamin D receptor and vitamin D status in patients with oral neoplasms and effect of vitamin D supplementation on quality of life in advanced cancer treatment. Contemp Oncol (Pozn). 2017;21(2):145–151. doi:10.5114/wo.2017.68623.
36. Bhanu A, Waghmare CM, Jain VS, Pawar HJ. Serum 25-hydroxy vitamin-D levels in head and neck cancer chemoradiation therapy: Potential in cancer therapeutics. Indian J Cancer. 2024;61(2):403–407. doi:10.4103/ijc.IJC_358_20.
37. Nasser NJ, Fenig S, Ravid A, et al. Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients. npj Breast Cancer. 2017;3:10. doi:10.1038/s41523-017-0006-x.
38. Fassio A, Porciello G, Carioli G, et al. Post-diagnosis serum 25-hydroxyvitamin D concentrations in women treated for breast cancer participating in a lifestyle trial in Italy. Reumatismo. 2024;76(1):21–34.
39. Männle H, Momm F, Münstedt K. Vitamin D and selenium blood levels and acute skin toxicity during radiotherapy for breast cancer. Complement Ther Med. 2020;49:102291. doi:10.1016/j.ctim.2019.102291.
40. Ghorbanzadeh-Moghaddam A, Gholamrezaei A, Hemati S. Vitamin D deficiency is associated with the severity of radiation-induced proctitis in cancer patients. Int J Radiat Oncol Biol Phys. 2015;92(3):613–618. doi:10.1016/j.ijrobp.2015.02.011.
41. Deng Z, Li M, Guo J, et al. Low serum 25-hydroxyvitamin D3 levels and late delayed radiation-induced brain injury in patients with nasopharyngeal carcinoma: A case–control study. Brain Behav. 2020;10(12):e01892. doi:10.1002/brb3.1892.
42. Deng Y, Fu Y, Feng G, Zhang Y. Vitamin D receptor polymorphisms associate with the efficacy and toxicity of radioiodine-131 therapy in patients with differentiated thyroid cancer. Cancer Biomark. 2024;41(1):133–143. doi:10.3233/CBM-230566.
43. Nejatinamini S, Debenham BJ, Clugston RD, et al. Poor vitamin status is associated with skeletal muscle loss and mucositis in head and neck cancer patients. Nutrients. 2018;10(9):1236. doi:10.3390/nu10091236.
44. Suardi D, Judistiani RTD, Rinaldi M, et al. Impact of Cholecalciferol Supplementation on Radiotherapy Outcomes in Advanced Cervical Cancer. Med Sci Monit. 2025;31:e945964. Published 2025 Mar 24. doi:10.12659/MSM.945964
45. Yamada D, Eguchi H, Iwagami Y, et al. Patients treated with preoperative chemoradiation for pancreatic ductal adenocarcinoma have impaired bone density, a predictor of distant metastasis. Ann Surg Oncol. 2017;24(11):3715–3724. doi:10.1245/s10434-017-6040-y.
46. Nguyen CV, Lu KQ. Vitamin D3 and its potential to ameliorate chemical and radiation-induced skin injury during cancer therapy. Disaster Med Public Health Prep. 2024;18(e4):1–3. doi:10.1017/dmp.2023.211.
47. Nguyen CV, Zheng L, Lu KQ. High-dose vitamin D for the management of acute radiation dermatitis. JAAD Case Rep. 2023;39:47–50. doi:10.1016/j.jdcr.2023.06.003.
48. Reiter M, Goda A, Kwon Y, et al. Nutritional status and vitamin D supplementation in breast cancer patients receiving chemotherapy: Results from a phase II clinical trial. Clin Nutr ESPEN. 2024;57:149–156.
49. Wu CC, Wu X, Wells A, et al. Vitamin D in cancer treatment: Molecular mechanisms and therapeutic potential. Front Pharmacol. 2019;10:984. doi:10.3389/fphar.2019.00984.
50. National Cancer Institute. Vitamin D and Cancer Prevention. Updated February 1, 2024. Accessed April 6, 2025. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/vitamin-d-fact-sheet
51. Peh HY, Tan WS, Liao W, Wong WS. Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol. Pharmacol Ther. 2016;162:152-169. doi:10.1016/j.pharmthera.2015.12.003
52. Constantinou C, Charalambous C, Kanakis D. Vitamin E and cancer: an update on the emerging role of γ and δ tocotrienols. Eur J Nutr. 2020;59(3):845-857. doi:10.1007/s00394-019-01962-1
53. Islam MM, Sultana N, Liu C, Mao A, Katsube T, Wang B. Impact of dietary ingredients on radioprotection and radiosensitization: a comprehensive review. Ann Med. 2024;56(1):2396558. doi:10.1080/07853890.2024.2396558
54. Zhu YJ, Bo YC, Liu XX, et al. Association of dietary vitamin E intake with risk of lung cancer: a dose-response meta-analysis. Asia Pac J Clin Nutr. 2017;26(2):271–277. doi:10.6133/APJCN.032016.04.
55. Li XH, Fu D, Latif NH, et al. Delta-tocotrienol protects mouse and human hematopoietic progenitors from gamma-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling. Haematologica. 2010;95(12):1996-2004. doi:10.3324/haematol.2010.026492
56. Singh VK, Kulkarni S, Fatanmi OO, et al. Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates. Radiat Res. 2016;185(3):285-298. doi:10.1667/RR14127.1
57. Siveen KS, Ahn KS, Ong TH, et al. Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget. 2014;5(7):1897-1911. doi:10.18632/oncotarget.1876
58. Ghosh SP, Kulkarni S, Hieber K, et al. Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol. 2009;85(7):598-606. doi:10.1080/0955300
59. Kulkarni S, Ghosh SP, Satyamitra M, et al. Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation. Radiat Res. 2010;173(6):738-747. doi:10.1667/RR1824.1
60. Kulkarni SS, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP. Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor. Int Immunopharmacol. 2012;14(4):495-503. doi:10.1016/j.intimp.2012.09.001
61. Otluoglu GD, Yılmaz B, Ekinci G, Bayri Y, Bozkurt SU, Dağçınar A. Pentoxifylline and Vitamin E Can Restrict Radiation Necrosis via Vascular Pathways, Experimental Study in an Animal Model. World Neurosurg. 2023;179:e530-e538. doi:10.1016/j.wneu.2023.08.135
62. Anzai K, Ueno M, Matsumoto K, Ikota N, Takata J. Gamma-tocopherol-N,N-dimethylglycine ester as a potent post-irradiation mitigator against whole body X-irradiation-induced bone marrow death in mice. J Radiat Res. 2014;55(1):67-74. doi:10.1093/jrr/rrt094
63. Chung MK, Kim do H, Ahn YC, Choi JY, Kim EH, Son YI. Randomized Trial of Vitamin C/E Complex for Prevention of Radiation-Induced Xerostomia in Patients with Head and Neck Cancer. Otolaryngol Head Neck Surg. 2016;155(3):423-430. doi:10.1177/0194599816642418
64. Ferreira PR, Fleck JF, Diehl A, et al. Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: a double-blind randomized trial. Head Neck. 2004;26(4):313-321. doi:10.1002/hed.10382
65. Agha-Hosseini F, Pourpasha M, Amanlou M, Moosavi MS. Mouthwash Containing Vitamin E, Triamcinolon, and Hyaluronic Acid Compared to Triamcinolone Mouthwash Alone in Patients With Radiotherapy-Induced Oral Mucositis: Randomized Clinical Trial. Front Oncol. 2021;11:614877. Published 2021 Mar 11. doi:10.3389/fonc.2021.614877
66. Jacobson G, Bhatia S, Smith BJ, Button AM, Bodeker K, Buatti J. Randomized trial of pentoxifylline and vitamin E vs standard follow-up after breast irradiation to prevent breast fibrosis, evaluated by tissue compliance meter. Int J Radiat Oncol Biol Phys. 2013;85(3):604-608. doi:10.1016/j.ijrobp.2012.06.042
67. Kaidar-Person O, Marks LB, Jones EL. Pentoxifylline and vitamin E for treatment or prevention of radiation-induced fibrosis in patients with breast cancer. Breast J. 2018;24(5):816-819. doi:10.1111/tbj.13044
68. Sayed R, El Wakeel L, Saad AS, Kelany M, El-Hamamsy M. Pentoxifylline and vitamin E reduce the severity of radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients: a randomized, controlled study. Med Oncol. 2019;37(1):8. Published 2019 Nov 21. doi:10.1007/s12032-019-1334-5
69. Queiroz Schmidt FM, Serna González CV, Mattar RC, Lopes LB, Santos MF, Santos VLCG. Topical application of a cream containing nanoparticles with vitamin E for radiodermatitis prevention in women with breast cancer: A randomized, triple-blind, controlled pilot trial. Eur J Oncol Nurs. 2022;61:102230. doi:10.1016/j.ejon.2022.102230
70. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the Risk of Prostate Cancer: Updated Results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549–1556.
71. Springett GM, Husain K, Neuger A, et al. A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia. EBioMedicine. 2015;2(12):1987-1995. Published 2015 Nov 14. doi:10.1016/j.ebiom.2015.11.025
72. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?. J Natl Cancer Inst. 2008;100(11):773-783. doi:10.1093/jnci/djn148
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Ada Wiśniowska, Maksymilian Wiśniowski, Kacper Buczek, Aleksandra Kozłowska
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 14
Number of citations: 0
