Phytochemicals as Radioprotective and Radiosensitizing Agents in Cancer Radiotherapy: Advances, Challenges, and Future Perspectives

Abstract

Radiation therapy (RT) remains a fundament of cancer treatment, yet its effectiveness is often hindered by normal tissue toxicity and radiation-induced fibrosis. Recent research has highlighted the promise of bioactive-phytochemicals in enhancing the therapeutic index of RT-sensitizing tumor cells to radiation while safeguarding healthy tissues. This reflects a growing interest in integrating natural compounds with conventional cancer therapies to achieve synergistic effects. To summarize recent advances, identify the research gaps, and evaluate future directions, a comprehensive review was conducted using data from the NCBI and PubChem databases, focusing on preclinical and clinical studies exploring the role of phytochemicals in cancer radiotherapy. The findings stated that the phytochemicals such as curcumin, resveratrol, quercetin, genistein, and EGCG have been shown to sensitize cancer cells to radiation by amplifying DNA damage, promoting apoptosis, and inhibiting key signaling pathways including PI3K/Akt, ATM, and NF-κB. Simultaneously, these compounds exhibit protective effects on normal tissues by activating antioxidant responses (e.g., Nrf2/ARE), reducing oxidative stress, and alleviating radiation-induced fibrosis through modulation of CTGF and TGF-β pathways. Emerging agents like astilbin, puerarin, and isorhamnetin have also demonstrated notable radiosensitizing and antifibrotic potential. However, challenges such as poor bioavailability, dose inconsistencies, and patient-specific variability remain significant barriers to clinical translation. In conclusion, the dual context-dependent actions of phytochemicals emphasize the need for personalized therapeutic strategies, optimized dosing, and advanced delivery systems. Furthermore, integrating nanotechnology may hold particular promise for enhancing the precision and effectiveness of phytochemical-based interventions in radiation oncology.

Keywords

phytochemicals - radioprotector - radiosensitizer - personalized medicine - cancers

Publikationsverlauf

Eingereicht: 10. Juni 2025

Angenommen nach Revision: 14. Oktober 2025

Accepted Manuscript online:
14. Oktober 2025

Artikel online veröffentlicht:
17. November 2025

• References

• 1 Mehta SR, Suhag V, Semwal M, Sharma N. Radiotherapy: Basic concepts and recent advances. Med J Armed Forces India 2010; 66: 158-162
• 2 Wang J, Wang H, Qian H. Biological effects of radiation on cancer cells. Mil Med Res 2018; 5: 20
• 3 Poland S, Ebina W, Muggia F, Guth A. Breast radiation-associated secondary malignancies: A review. Clin Surg Oncol 2023; 2: 100010
• 4 Debela DT, Muzazu SG, Heraro KD, Ndalama MT, Mesele BW, Haile DC, Kitui SK, Manyazewal T. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med 2021; 9: 20503121211034366
• 5 Cronin KA, Scott S, Firth AU, Sung H, Henley SJ, Sherman RL, Siegel RL, Anderson RN, Kohler BA, Benard VB, Negoita S, Wiggins C, Cance WG, Jemal A. Annual report to the nation on the status of cancer, part 1: National cancer statistics. Cancer 2022; 128: 4251-4284
• 6 Nogueira RMP, Vital FMR, Bernabé DG, Carvalho MB. Interventions for radiation-induced fibrosis in patients with breast cancer: Systematic review and meta-analyses. Adv Radiat Oncol 2022; 7: 100912
• 7 Fijardo M, Kwan JYY, Bissey PA, Citrin DE, Yip KW, Liu FF. The clinical manifestations and molecular pathogenesis of radiation fibrosis. eBioMedicine 2024; 103: 105089
• 8 Asgharian P, Tazekand AP, Hosseini K, Forouhandeh H, Ghasemnejad T, Ranjbar M, Hasan M, Kumar M, Beirami SM, Tarhriz V, Soofiyani SR, Kozhamzharova L, Sharifi-Rad J, Calina D, Cho WC. Potential mechanisms of quercetin in cancer prevention: Focus on cellular and molecular targets. Cancer Cell Int 2022; 22: 257
• 9 Mundekkad D, Cho WC. Applications of curcumin and its nanoforms in the treatment of cancer. Pharmaceutics 2023; 15: 2223
• 10 Choi S, Shin M, Kim WY. Targeting the DNA damage response (DDR) of cancer cells with natural compounds derived from Panax ginseng and other plants. J Ginseng Res 2025; 49: 1-11
• 11 Jiang J, Yang Y, Wang F, Mao W, Wang Z, Liu Z. Quercetin inhibits breast cancer cell proliferation and survival by targeting Akt/mTOR/PTEN signaling pathway. Chem Biol Drug Des 2024; 103: e14557
• 12 Cui J, Li H, Zhang T, Lin F, Chen M, Zhang G, Feng Z. Research progress on the mechanism of curcumin anti-oxidative stress based on signaling pathway. Front Pharmacol 2025; 16: 1548073
• 13 Hussar P. Apoptosis regulators Bcl-2 and caspase-3. Encyclopedia 2022; 2: 1624-1636
• 14 Purkayastha A, Sharma N, Sarin A, Bhatnagar S, Chakravarty N, Mukundan H, Suhag V, Singh S. Radiation fibrosis syndrome: The evergreen menace of radiation therapy. Asia-Pac J Oncol Nurs 2019; 6: 238-245
• 15 Kumar A, Nirmal P, Kumar M, Jose A, Tomer V, Oz E, Proestos C, Zeng M, Elobeid T, Sneha K, Oz F. Major phytochemicals: Recent advances in health benefits and extraction method. Molecules 2023; 28: 887
• 16 Ramesh P, Jagadeesan R, Sekaran S, Dhanasekaran A, Vimalraj S. Flavonoids: Classification, function, and molecular mechanisms involved in bone remodelling. Front Endocrinol 2021; 12: 779638
• 17 Thiruvengadam M, Venkidasamy B, Subramanian U, Samynathan R, Ali Shariati M, Rebezov M, Girish S, Thangavel S, Dhanapal AR, Fedoseeva N, Lee J, Chung IM. Bioactive compounds in oxidative stress-mediated diseases: Targeting the NRF2/ARE signaling pathway and epigenetic regulation. Antioxidants 2021; 10: 1859
• 18 Lee SC, Jee SC, Kim M, Kim S, Shin MK, Kim Y, Sung JS. Curcumin suppresses the lipid accumulation and oxidative stress induced by Benzo[a]pyrene toxicity in HepG2 cells. Antioxidants 2021; 10: 1314
• 19 Forni C, Facchiano F, Bartoli M, Pieretti S, Facchiano A, DʼArcangelo D, Norelli S, Valle G, Nisini R, Beninati S, Tabolacci C, Jadeja RN. Beneficial role of phytochemicals on oxidative stress and age-related diseases. Biomed Res Int 2019; 2019: 1-16
• 20 Montoro A, Obrador E, Mistry D, Forte GI, Bravatà V, Minafra L, Calvaruso M, Cammarata FP, Falk M, Schettino G, Ahire V, Daems N, Boterberg T, Dainiak N, Chaudhary P, Baatout S, Mishra KP. Radioprotectors, Radiomitigators, and Radiosensitizers. In: Baatout S. Hrsg. Radiobiology Textbook. Cham: Springer International Publishing; 2023: 571-628
• 21 Stasiłowicz-Krzemień A, Gościniak A, Formanowicz D, Cielecka-Piontek J. Natural guardians: Natural compounds as radioprotectors in cancer therapy. Int J Mol Sci 2024; 25: 6937
• 22 Kaiser AE, Baniasadi M, Giansiracusa D, Giansiracusa M, Garcia M, Fryda Z, Wong TL, Bishayee A. Sulforaphane: A broccoli bioactive phytocompound with cancer preventive potential. Cancers (Basel) 2021; 13: 4796
• 23 Hammad M, Raftari M, Cesário R, Salma R, Godoy P, Emami SN, Haghdoost S. Roles of oxidative stress and Nrf2 signaling in pathogenic and non-pathogenic cells: A possible general mechanism of resistance to therapy. Antioxidants 2023; 12: 1371
• 24 Wani AK, Akhtar N, Mir TUG, Singh R, Jha PK, Mallik SK, Sinha S, Tripathi SK, Jain A, Jha A, Devkota HP, Prakash A. Targeting apoptotic pathway of cancer cells with phytochemicals and plant-based nanomaterials. Biomolecules 2023; 13: 194
• 25 Komorowska D, Radzik T, Kalenik S, Rodacka A. Natural radiosensitizers in radiotherapy: Cancer treatment by combining ionizing radiation with resveratrol. Int J Mol Sci 2022; 23: 10627
• 26 Klieber N, Hildebrand LS, Faulhaber E, Fionda G, Schmid TE, Paszkowski-Rogacz M, Berger A, Müller F, van Lier H, Knoll T, Wagner S, Schäfer N. Different impacts of DNA-PK and mTOR kinase inhibitors in combination with ionizing radiation on HNSCC and normal tissue cells. Cells 2024; 13: 304
• 27 Nisar S, Masoodi T, Prabhu KS, Kuttikrishnan S, Zarif L, Khatoon S, Ali S, Uddin S, Akil A, Singh M, Koul S. Natural products as chemo-radiation therapy sensitizers in cancers. Biomed Pharmacother 2022; 154: 113610
• 28 Nickoloff JA, Boss MK, Allen CP, Godoy-Rouanet B. Translational research in radiation-induced DNA damage signaling and repair. Transl Cancer Res 2017; 6: S875
• 29 Hussar P. Apoptosis regulators Bcl-2 and Caspase-3. Encyclopedia 2022; 2: 1624-1636
• 30 Sharifi-Rad J, Rayess YE, Rizk AA, Sadek KM, Nader MA, Fadhal E, Goswami P, Elshazly SM, Luqman S, El-Sayed WS, Eid HM, Polito L, Filosa R, Nabavi SF, Aberkane A. Turmeric and its major compound curcumin on health: Bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front Pharmacol 2020; 11: 01021
• 31 Dong L, He J, Luo L, Wang K. Targeting the interplay of autophagy and ROS for cancer therapy: An updated overview on phytochemicals. Pharmaceuticals (Basel) 2023; 16: 92
• 32 He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6: 425
• 33 Liu H, Liu K, Huang Z, Park CM, Thimmegowda NR, Jang JH, Ryoo IJ, He L, Kim SO, Oi N, Lee KW, Soung NK, Bode AM, Yang Y, Zhou X, Erikson RL, Ahn JS, Hwang J, Kim KE, Dong Z, Kim BY. A chrysin derivative suppresses skin cancer growth by inhibiting cyclin-dependent kinases. J Biol Chem 2013; 288: 25924-25937
• 34 Islam MR, Rauf A, Akash S, Trisha SI, Nasim AH, Akter M, Dhar PS, Ogaly HA, Hemeg HA, Wilairatana P, Thiruvengadam M. Targeted therapies of curcumin focus on its therapeutic benefits in cancers and human health: Molecular signaling pathway-based approaches and future perspectives. Biomed Pharmacother 2024; 170: 116034
• 35 Kapała A, Szlendak M, Motacka E. The anti-cancer activity of lycopene: A systematic review of human and animal studies. Nutrients 2022; 14: 5152
• 36 Frangogiannis NG. Transforming growth factor–β in tissue fibrosis. J Exp Med 2020; 217: e20190103
• 37 Chung JY, Chan MK, Li JS, Chan AS, Tang PC, Leung KT, To KF, Lan HY, Tang PM. TGF-β signaling: From tissue fibrosis to tumor microenvironment. Int J Mol Sci 2021; 22: 7575
• 38 Luo J, Deng L, Zou H, Guo Y, Tong T, Huang M, Ling G, Li P. New insights into the ambivalent role of YAP/TAZ in human cancers. J Exp Clin Cancer Res 2023; 42: 130
• 39 Effendi WI, Nagano T. Connective tissue growth factor in idiopathic pulmonary fibrosis: Breaking the bridge. Int J Mol Sci 2022; 23: 6064
• 40 Shi Z, Zhou Z. MST kinases in innate immune signaling. Cell Stress 2018; 2: 4-13
• 41 Bickelhaupt S, Erbel C, Timke C, Wirkner U, Dadrich M, Flechsig P, Tietz A, Pföhler J, Gross W, Peschke P, Hoeltgen L, Katus HA, Gröne HJ, Nicolay NH, Saffrich R, Debus J, Sternlicht MD, Seeley TW, Lipson KE, Huber PE. Effects of CTGF blockade on attenuation and reversal of radiation-induced pulmonary fibrosis. JNCI 2017; 109
• 42 Groves AM, Johnston CJ, Williams JP, Finkelstein JN. Role of infiltrating monocytes in the development of radiation-induced pulmonary fibrosis. Radiat Res 2018; 189: 300
• 43 Avila-Carrasco L, Majano P, Sánchez-Toméro JA, Selgas R, López-Cabrera M, Aguilera A, González Mateo G. Natural plants compounds as modulators of epithelial-to-mesenchymal transition. Front Pharmacol 2019; 10: 715
• 44 Talib WH, Alsayed AR, Barakat M, Abu-Taha MI, Mahmod AI. Targeting drug chemo-resistance in cancer using natural products. Biomedicines 2021; 9: 1353
• 45 Cione E, La Torre C, Cannataro R, Navarra M, Ricciardiello F, Richeldi L, Ardizzoni A, Fazia M, Fasano S, Di Nicuolo F. Quercetin, epigallocatechin gallate, curcumin, and resveratrol: from dietary sources to human MicroRNA modulation. Molecules 2019; 25: 63
• 46 Fan J, Wei S, Zhang X, Wang T, Cheng L, Tao S, Liu S. Resveratrol inhibits TGF-β1–induced fibrotic effects in human pterygium fibroblasts. Environ Health Prev Med 2023; 28: 59
• 47 Ramos-Tovar E, Muriel P. Molecular mechanisms that link oxidative stress, inflammation, and fibrosis in the liver. Antioxidants 2020; 9: 1279
• 48 Kashyap D, Garg VK, Tuli HS, Yerer MB. Fisetin and quercetin: Promising flavonoids with chemopreventive potential. Biomolecules 2019; 9: 174
• 49 Suzuki T, Ohishi T, Tanabe H, Miyata R, Lam M, Hida T, Itoh S, Miyamoto T, Udagawa H. Anti-inflammatory effects of dietary polyphenols through inhibitory activity against metalloproteinases. Molecules 2023; 28: 5426
• 50 Guillermin O, Angelis N, Sidor CM, Ridgway R, Baulies A, Kucharska A, Antas P, Rose MR, Cordero J, Sansom O, Li VSW, Thompson BJ. Wnt and Src signals converge on YAP‐TEAD to drive intestinal regeneration. EMBO J 2021; 40: e105770
• 51 Zhong Z, Jiao Z, Yu FX. The Hippo signaling pathway in development and regeneration. Cell Rep 2024; 43: 113926
• 52 Ouellette MM, Zhou S, Yan Y. Cell signaling pathways that promote radioresistance of cancer cells. Diagnostics 2022; 12: 656
• 53 Xiao Y, Dong J. The hippo signaling pathway in cancer: A cell cycle perspective. Cancers (Basel) 2021; 13: 6214
• 54 Mokhtari RB, Ashayeri N, Baghaie L, Sambi M, Satari K, Baluch N, Bosykh DA, Szewczuk MR, Chakraborty S. The hippo pathway effectors YAP/TAZ-TEAD oncoproteins as emerging therapeutic targets in the tumor microenvironment. Cancers (Basel) 2023; 15: 3468
• 55 Ortega Á, Vera I, Diaz MP, Navarro C, Rojas M, Torres W, Parra H, Salazar J, De Sanctis JB, Bermúdez V. The YAP/TAZ signaling pathway in the tumor microenvironment and carcinogenesis: Current knowledge and therapeutic promises. Int J Mol Sci 2021; 23: 430
• 56 Choudhari AS, Mandave PC, Deshpande M, Ranjekar P, Prakash O. Phytochemicals in cancer treatment: From preclinical studies to clinical practice. Front Pharmacol 2020; 10: 1614
• 57 Samanta SK, Kandimalla R, Gogoi B, Dutta KN, Choudhury P, Deb PK, Devi R, Pal BC, Talukdar NC. Phytochemical portfolio and anticancer activity of Murraya koenigii and its primary active component, mahanine. Pharmacol Res 2018; 129: 227-236
• 58 Sohn SI, Priya A, Balasubramaniam B, Muthuramalingam P, Sivasankar C, Selvaraj A, Valliammai A, Jothi R, Pandian S. Biomedical applications and bioavailability of curcumin–An updated overview. Pharmaceutics 2021; 13: 2102
• 59 Sharifi-Rad J, Rayess YE, Rizk AA, Sadek KM, Nader MA, Fadhal E, Goswami P, Elshazly SM, Luqman S, El-Sayed WS, Eid HM, Polito L, Filosa R, Nabavi SF, Aberkane A. Turmeric and its major compound curcumin on health: Bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front Pharmacol 2020; 11: 01021
• 60 Golonko A, Pienkowski T, Swislocka R, Trzeciak HI, Morawiec E, Wasek M, Winiarska M, Mazurkiewicz Z, Bujko M. Dietary factors and their influence on immunotherapy strategies in oncology: a comprehensive review. Cell Death Dis 2024; 15: 254
• 61 Zhang H, Shan Y, Wu Y, Zhang Y, Wu YL, Guo Q. Berberine suppresses LPS-induced inflammation through modulating Sirt1/NF-κB signaling pathway in RAW264.7 cells. Int Immunopharmacol 2017; 52: 93-100