Oxidative Stress Biomarkers in Doxorubicin-Induced Multi-Organ Toxicity: Mechanisms, Clinical Relevance and Emerging Protective Strategies
DOI:
https://doi.org/10.33003/fjs-2026-1016-5821Keywords:
Doxorubicin, Oxidative stress, Biomarkers, Multi-organ toxicity, Reactive oxygen species, ChemotherapyAbstract
Doxorubicin is an effective anthracycline used against solid and haematological malignancies, but dose-dependent multi-organ toxicity limits its clinical use. Oxidative stress is a major mechanism underlying this injury and produces measurable changes in redox biomarkers. This review synthesises evidence on mechanisms of doxorubicin-induced oxidative stress, major biomarkers, organ-specific patterns, clinical relevance and protective strategies. PubMed/MEDLINE, targeted Google Scholar searching and backward reference-list searching were used to identify literature from January 2010 to 10 August 2026. Relevant human, animal and in-vitro studies were considered, with seminal pre-2010 studies retained selectively for mechanistic context. Doxorubicin generally increases oxidative-damage markers, particularly malondialdehyde and 8-hydroxy-2′-deoxyguanosine, while reducing superoxide dismutase, catalase, glutathione peroxidase and glutathione. Evidence is strongest for cardiotoxicity, whereas clinical validation for non-cardiac organs is limited. Dexrazoxane and liposomal doxorubicin have stronger clinical evidence for cardioprotection, while many antioxidant and nanocarrier approaches remain preclinical. Oxidative-stress biomarkers are mechanistically informative but lack sufficient standardisation and prospective validation for routine predictive use. Integrated biomarker approaches require further clinical evaluation.
References
Abdeahad, H., Moreno, D. G., Bloom, S. I., Norman, L., Lesniewski, L. A., & Donato, A. J. (2025). MitoQ reduces senescence burden in doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage. American Journal of Physiology-Heart and Circulatory Physiology, 329(5), H1154–H1161. https://doi.org/10.1152/ajpheart.00568.2025
Arafa, M. H., Mohammad, N. S., Atteia, H. H., & Abd-Elaziz, H. R. (2014). Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats. Journal of Physiology and Biochemistry, 70(3), 701–711. https://doi.org/10.1007/s13105-014-0339-y
Aslan, İ. Ö., Öz, M., Erdal, H., Karaboğa, İ., & Doğan, M. (2025). Protective effect of N-acetylcysteine in doxorubicin-induced primary ovarian failure in female rats. Turkish Journal of Obstetrics and Gynecology, 22(3), 266–274. https://doi.org/10.4274/tjod.galenos.2025.71654
Belhan, S., Özkaraca, M., Özdek, U., & Kömüroğlu, A. U. (2020). Protective role of chrysin on doxorubicin-induced oxidative stress and DNA damage in rat testes. Andrologia, 52(9), e13747. https://doi.org/10.1111/and.13747
Benzer, F., Kandemir, F. M., Ozkaraca, M., Kucukler, S., & Caglayan, C. (2018). Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. Journal of Biochemical and Molecular Toxicology, 32(2), e22030. https://doi.org/10.1002/jbt.22030
Cardoso, C. V., de Barros, M. P., Bachi, A. L. L., Bernardi, M. M., Kirsten, T. B., Martins, M. F. M., Rocha, P. R. D., Rodrigues, P. S., & Bondan, E. F. (2020). Chemobrain in rats: Behavioral, morphological, oxidative and inflammatory effects of doxorubicin administration. Behavioural Brain Research, 378, 112233. https://doi.org/10.1016/j.bbr.2019.112233
Chicco, A. J., Schneider, C. M., & Hayward, R. (2006). Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. Journal of Cardiovascular Pharmacology, 47(2), 182–189. https://doi.org/10.1097/01.fjc.0000199682.43448.2d
Diaz De Leon, J. A., & Borges, C. R. (2020). Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. Journal of Visualized Experiments, (159), e61122. https://doi.org/10.3791/61122
Fang, X., Wang, H., Han, D., Xie, E., Yang, X., Wei, J., Gu, S., Gao, F., Zhu, N., Yin, X., Cheng, Q., Zhang, P., Dai, W., Chen, J., Yang, F., Yang, H.-T., Linkermann, A., Gu, W., Min, J., & Wang, F. (2019). Ferroptosis as a target for protection against cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 116(7), 2672–2680. https://doi.org/10.1073/pnas.1821022116
Harris, L., Batist, G., Belt, R., Rovira, D., Navari, R., Azarnia, N., Welles, L., Winer, E., & TLC D-99 Study Group. (2002). Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer, 94(1), 25–36. https://doi.org/10.1002/cncr.10201
Igbashio, M. D., Eluehike, N., & Oriakhi, K. (2025). Liver function and biomarkers of oxidative stress levels in streptozotocin-induced diabetic rats treated with leaves extract of Carica papaya. FUDMA Journal of Sciences, 9(5), 222–231. https://doi.org/10.33003/fjs-2025-0905-3665
Ichikawa, Y., Ghanefar, M., Bayeva, M., Wu, R., Khechaduri, A., Naga Prasad, S. V., Mutharasan, R. K., Naik, T. J., & Ardehali, H. (2014). Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The Journal of Clinical Investigation, 124(2), 617–630. https://doi.org/10.1172/JCI72931
Il’yasova, D., Mixon, G., Wang, F., Marcom, P. K., Marks, J., Spasojevich, I., Craft, N., Arredondo, F., & DiGiulio, R. (2009). Markers of oxidative status in a clinical model of oxidative assault: A pilot study in human blood following doxorubicin administration. Biomarkers, 14(5), 321–325. https://doi.org/10.1080/13547500902946757
Il’yasova, D., Spasojević, I., Wang, F., Tolun, A. A., Baše, K., Young, S. P., Marcom, P. K., Marks, J. R., Mixon, G., DiGiulio, R. T., & Millington, D. S. (2010). Urinary biomarkers of oxidative status in a clinical model of oxidative assault. Cancer Epidemiology, Biomarkers & Prevention, 19(6), 1506–1510. https://doi.org/10.1158/1055-9965.EPI-10-0211
Kim, N., Kwon, S., Kwon, G., Song, N., Jo, H., Kim, C., Park, S., & Lee, D. (2024). Tumor-targeted and stimulus-responsive polymeric prodrug nanoparticles to enhance the anticancer therapeutic efficacy of doxorubicin. Journal of Controlled Release, 369, 351–362. https://doi.org/10.1016/j.jconrel.2024.03.046
Kumral, A., Giriş, M., Soluk-Tekkeşin, M., Olgaç, V., Doğru-Abbasoğlu, S., Türkoğlu, Ü. & Uysal, M. (2015). Effect of olive leaf extract treatment on doxorubicin-induced cardiac, hepatic and renal toxicity in rats. Pathophysiology, 22(2), 117–123. https://doi.org/10.1016/j.pathophys.2015.04.002
Kumar, L., Vijayvergiya, R., Jain, A., Singh, C., Jain, A., Prakash, G., Khadwal, A., & Malhotra, P. (2025). Incidence, risk factors and early prediction of doxorubicin-induced cardiotoxicity by global longitudinal strain and cardiac biomarkers in Indian patients with lymphoma: A prospective observational study. Clinical Lymphoma, Myeloma & Leukemia, 25(3), e143–e150. https://doi.org/10.1016/j.clml.2024.10.008
Kwatra, M., Kumar, V., Jangra, A., Mishra, M., Ahmed, S., Ghosh, P., Vohora, D., & Khanam, R. (2016). Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. Pharmaceutical Biology, 54(4), 637–647. https://doi.org/10.3109/13880209.2015.1070879
Lyu, Y. L., Kerrigan, J. E., Lin, C. P., Azarova, A. M., Tsai, Y. C., Ban, Y., & Liu, L. F. (2007). Topoisomerase IIβ mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Research, 67(18), 8839–8846. https://doi.org/10.1158/0008-5472.CAN-07-1649
Marty, M., Espié, M., Llombart, A., Monnier, A., Rapoport, B. L., Stahalova, V., & Dexrazoxane Study Group. (2006). Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Annals of Oncology, 17(4), 614–622. https://doi.org/10.1093/annonc/mdj134
O’Brien, M. E. R., Wigler, N., Inbar, M., Rosso, R., Grischke, E., Santoro, A., Catane, R., Kieback, D. G., Tomczak, P., Ackland, S. P., Orlandi, F., Mellars, L., Alland, L., Tendler, C., & CAELYX Breast Cancer Study Group. (2004). Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Annals of Oncology, 15(3), 440–449. https://doi.org/10.1093/annonc/mdh097
Polomski, E. A. S., Speetjens, F. M., Jukema, J. W., Heemelaar, J. C., van de Sande, M. A. J., Gelderblom, H., & Antoni, M. L. (2026). Asymptomatic cardiotoxicity after high-dose anthracycline treatment in sarcoma patients assessed by biomarkers and echocardiography. International Journal of Cancer, Advance online publication. https://doi.org/10.1002/ijc.70620
Radeva, L., & Yoncheva, K. (2025). Doxorubicin toxicity and recent approaches to alleviating its adverse effects with focus on oxidative stress. Molecules, 30(15), 3311. https://doi.org/10.3390/molecules30153311
Renu, K., & Gopalakrishnan, A. V. (2019). Deciphering the molecular mechanism during doxorubicin-mediated oxidative stress and apoptosis through Nrf2 and PGC-1α in a rat testicular milieu. Reproductive Biology, 19(1), 22–37. https://doi.org/10.1016/j.repbio.2019.02.004
Sritharan, S., & Sivalingam, N. (2025). A recent decade update on combating doxorubicin-induced toxicities. Archives of Toxicology, 99(9), 3565–3578. https://doi.org/10.1007/s00204-025-04112-1
Swain, S. M., Whaley, F. S., & Ewer, M. S. (2003). Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer, 97(11), 2869–2879. https://doi.org/10.1002/cncr.11407
Taherkhani, M., Mahjoub, S., Moslemi, D., & Karkhah, A. (2017). Three cycles of AC chemotherapy regimen increased oxidative stress in breast cancer patients: A clinical hint. Caspian Journal of Internal Medicine, 8(4), 264–268. https://doi.org/10.22088/cjim.8.4.264
Tulubas, F., Gurel, A., Oran, M., Topcu, B., Caglar, V., & Uygur, E. (2015). The protective effects of omega-3 fatty acids on doxorubicin-induced hepatotoxicity and nephrotoxicity in rats. Toxicology and Industrial Health, 31(7), 638–644. https://doi.org/10.1177/0748233713483203
Zhang, S., Liu, X., Bawa-Khalfe, T., Lu, L. S., Lyu, Y. L., Liu, L. F., & Yeh, E. T. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Medicine, 18(11), 1639–1642. https://doi.org/10.1038/nm.2919
Zhao, Y., Miriyala, S., Miao, L., Mitov, M., Schnell, D., Dhar, S. K., Cai, J., Klein, J. B., Sultana, R., Butterfield, D. A., Vore, M., Batinic-Haberle, I., Bondada, S., & St Clair, D. K. (2014). Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment. Free Radical Biology and Medicine, 72, 55–65. https://doi.org/10.1016/j.freeradbiomed.2014.03.001
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