mesЭкстремальная биомедицинаExtreme Medicine3033-89643033-8972Centre for Strategic Planning of the Federal Medical and Biological Agency10.47183/mes.2025-427mes-427Research ArticleНЕЙРОТЕХНОЛОГИИNEUROTECHNOLOGYПерспективы разработки терапии глиобластомы с применением редокс-таргетирующих препаратов: описательный обзорProspects for developing glioblastoma therapy using redox-targeting drugs: A narrative literature reviewhttps://orcid.org/0009-0003-4931-2574БулгаковТ. К.BulgakovT. K.

Булгаков Тимофей Кириллович

Москва

Timofei K. Bulgakov

Moscow

locusts2001@gmail.comhttps://orcid.org/0009-0008-3161-7333СтарцеваЛ. А.StartsevaL. A.

Старцева Лада Андреевна

Москва

Lada A. Startseva

Moscow

ladastartseva@gmail.comhttps://orcid.org/0000-0002-9340-2636КордюковаМ. Ю.KordyukovaM. Yu.

Кордюкова Мария Юрьевна, канд. биол. наук

Москва

Maria Yu. Kordyukova, Cand. Sci. (Biol.)

Moscow

kordyukova.maria@yahoo.comhttps://orcid.org/0000-0003-3729-8827ШевченкоЕ. К.ShevchenkoE. K.

Шевченко Евгений Константинович, канд. биол. наук

Москва

Evgeny K. Shevchenko, Cand. Sci. (Biol.)

Moscow

dr.eshevchenko@gmail.comhttps://orcid.org/0000-0001-6637-8098БелоусовВ. В.BelousovV. V.

Белоусов Всеволод Владимирович, д-р биол. наук

Москва

Vsevolod V. Belousov, Dr. Sci. (Biol.)

Moscow

vsevolod.belousov@gmail.comФедеральный центр мозга и нейротехнологий Федерального медико-биологического агентстваРоссияFederal Center of Brain Research and NeurotechnologiesRussian FederationРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian FederationФедеральный центр мозга и нейротехнологий Федерального медико-биологического агентства; Российский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияFederal Center of Brain Research and Neurotechnologies; Pirogov Russian National Research Medical UniversityRussian Federation202610062026282258266Copyright © Булгаков Т.К., Старцева Л.А., Кордюкова М.Ю., Шевченко Е.К., Белоусов В.В., 20262026Булгаков Т.К., Старцева Л.А., Кордюкова М.Ю., Шевченко Е.К., Белоусов В.В.Bulgakov T.K., Startseva L.A., Kordyukova M.Y., Shevchenko E.K., Belousov V.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.extrememedicine.ru/jour/article/view/427Введение

Введение. Глиобластома является наиболее распространенной первичной злокачественной опухолью головного мозга у взрослых. Это заболевание, как правило, имеет неблагоприятный прогноз: медианная продолжительность жизни пациентов после постановки диагноза — 14,6 месяца, несмотря на современное лечение, включающее в себя хирургическое удаление опухоли с последующей лучевой и химиотерапией. Во многом это обусловлено тем, что глиобластома характеризуется высокой резистентностью к химиотерапии. Одной из ключевых причин этого является устойчивость к окислительному стрессу.

Цель

Цель. Систематизация данных о редокс-зависимых механизмах развития химиорезистентности глиобластомы, а также анализ перспективы применения препаратов, дестабилизирующих редокс-гомеостаз, в терапии глиобластомы.

Обсуждение

Обсуждение. Клетки опухоли в ответ на действие терапии активируют антиоксидантные системы, тем самым сдерживая выброс активных форм кислорода, вызванного действием химиопрепаратов, стабилизируя внутриклеточный окислительно-восстановительный гомеостаз (редокс-гомеостаз) и предотвращая развитие окислительного стресса. В связи с этим применение соединений, обеспечивающих усиление генерации внутриклеточных активных форм кислорода либо подавляющих активность ключевых компонентов антиоксидантной защиты, представляется перспективным подходом для сенсибилизации опухоли к терапии. Ряд препаратов на основе таких соединений в качестве монотерапии либо в комбинации с другими подходами показывает свою эффективность в доклинических испытаниях и демонстрирует эффективность для терапии пациентов с глиобластомой в ходе клинических исследований.

Выводы

Выводы. Поиск более селективных ингибиторов антиоксидантных систем, оптимизация их доставки в опухоль и стратификация пациентов на основе молекулярно-генетических и биохимических маркеров редокс-гомеостаза опухоли может увеличить эффективность терапии глиобластомы.

Introduction

Introduction. Glioblastoma is the most common primary malignant brain tumor in adults. Despite modern treatment approaches involving surgical tumor resection followed by radiation and chemotherapy, the disease is typically associated with an unfavorable prognosis with the median survival of patients after diagnosis of about 14.6 months. This is largely attributable to the high chemoresistance of glioblastoma to therapy, determined, among other reasons, by its resistance to oxidative stress.

Objective

Objective. Generalization of data on redox-dependent mechanisms of glioblastoma chemoresistance, as well as an analysis of the prospects for using drugs that destabilize redox homeostasis in glioblastoma therapy.

Discussion

Discussion. In response to therapy, tumor cells activate antioxidant systems, thereby retaining the release of reactive oxygen species induced by chemotherapeutic agents, stabilizing intracellular redox homeostasis, and preventing the development of oxidative stress. In this regard, the use of compounds that enhance the generation of intracellular reactive oxygen species or suppress the activity of key components of antioxidant defense appears to be a promising approach for sensitizing tumors to therapy. A number of drugs based on such compounds, either as monotherapy or in combination with other approaches, have shown efficacy in preclinical trials and demonstrated effectiveness in treating patients with glioblastoma during clinical studies.

Conclusions

Conclusions. The search for more selective inhibitors of antioxidant systems, optimization of their delivery to the tumor, and patient stratification based on molecular-genetic and biochemical markers of tumor redox homeostasis could increase the effectiveness of glioblastoma therapy.

глиобластомахимиотерапияокислительный стрессантиоксидантные системыустойчивость к терапииglioblastomachemotherapyoxidative stressantioxidant systemstherapy resistanceработа выполнена в рамках государственного задания Федерального медико-биологического агентства № 123030700127-2 по теме: «Создание коллекции культур клеток злокачественной глиомы пациентов и разработка модели для скрининга терапевтических агентов».the work was performed within the framework of the state assignment of the Federal Medical and Biological Agency No. 123030700127-2 on the topic “Creation of a collection of malignant glioma cell cultures from patients and development of a model for screening therapeutic agents.”ReferencesWen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncology. 2020;22(8):1073–113. https://doi.org/10.1093/neuonc/noaa106Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncology. 2020;22(8):1073–113. https://doi.org/10.1093/neuonc/noaa106Dymova MA, Kuligina EV, Richter VA. Molecular Mechanisms of Drug Resistance in Glioblastoma. International Journal of Molecular Sciences. 2021;22(12):6385. https://doi.org/10.3390/ijms22126385Dymova MA, Kuligina EV, Richter VA. Molecular Mechanisms of Drug Resistance in Glioblastoma. International Journal of Molecular Sciences. 2021;22(12):6385. https://doi.org/10.3390/ijms22126385Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7Zhang J, Stevens MFG, Bradshaw TD. Temozolomide: Mechanisms of Action, Repair and Resistance. Current Molecular Pharmacology. 2012;5(1):102–14. https://doi.org/10.2174/1874467211205010102Zhang J, Stevens MFG, Bradshaw TD. Temozolomide: Mechanisms of Action, Repair and Resistance. Current Molecular Pharmacology. 2012;5(1):102–14. https://doi.org/10.2174/1874467211205010102Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes & Diseases. 2016;3(3):198–210. https://doi.org/10.1016/j.gendis.2016.04.007Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes & Diseases. 2016;3(3):198–210. https://doi.org/10.1016/j.gendis.2016.04.007Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. Journal of Clinical Oncology. 2013;31(32):4085–91. https://doi.org/10.1200/JCO.2013.49.6968Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. Journal of Clinical Oncology. 2013;31(32):4085–91. https://doi.org/10.1200/JCO.2013.49.6968Chien CH, Hsueh WT, Chuang JY, Chang KY. Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma. Journal of Biomedical Science. 2021;28(1):18. https://doi.org/10.1186/s12929-021-00717-7Chien CH, Hsueh WT, Chuang JY, Chang KY. Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma. Journal of Biomedical Science. 2021;28(1):18. https://doi.org/10.1186/s12929-021-00717-7Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma — a comprehensive review. Cancer Drug Resistance. 2021;4(1):17–43. https://doi.org/10.20517/cdr.2020.79Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma — a comprehensive review. Cancer Drug Resistance. 2021;4(1):17–43. https://doi.org/10.20517/cdr.2020.79Almeida Lima K, Osawa IYA, Ramalho MCC, de Souza I, Guedes CB, de Souza Filho CHD, et al. Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil. Biomedicines. 2023;11(4):1081. https://doi.org/10.3390/biomedicines11041081Almeida Lima K, Osawa IYA, Ramalho MCC, de Souza I, Guedes CB, de Souza Filho CHD, et al. Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil. Biomedicines. 2023;11(4):1081. https://doi.org/10.3390/biomedicines11041081Zhang W, Wang Z, Shu F, Jin Y, Liu H, Wang Q, et al. Activation of AMP-activated Protein Kinase by Temozolomide Contributes to Apoptosis in Glioblastoma Cells via p53 Activation and mTORC1 Inhibition*. Journal of Biological Chemistry. 2010;285(52):40461–71. https://doi.org/10.1074/jbc.M110.164046Zhang W, Wang Z, Shu F, Jin Y, Liu H, Wang Q, et al. Activation of AMP-activated Protein Kinase by Temozolomide Contributes to Apoptosis in Glioblastoma Cells via p53 Activation and mTORC1 Inhibition*. Journal of Biological Chemistry. 2010;285(52):40461–71. https://doi.org/10.1074/jbc.M110.164046Rocha CRR, Kajitani GS, Quinet A, Fortunato RS, Menck CFM. NRF2 and glutathione are key resistance mediators to temozolomide in glioma and melanoma cells. Oncotarget. 2016;7(30):48081–92. https://doi.org/10.18632/oncotarget.10129Rocha CRR, Kajitani GS, Quinet A, Fortunato RS, Menck CFM. NRF2 and glutathione are key resistance mediators to temozolomide in glioma and melanoma cells. Oncotarget. 2016;7(30):48081–92. https://doi.org/10.18632/oncotarget.10129Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nature Reviews. Molecular Cell Biology. 2020;21(7):363–83. https://doi.org/10.1038/s41580-020-0230-3Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nature Reviews. Molecular Cell Biology. 2020;21(7):363–83. https://doi.org/10.1038/s41580-020-0230-3Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biology. 2017;11:613–9. https://doi.org/10.1016/j.redox.2016.12.035Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biology. 2017;11:613–9. https://doi.org/10.1016/j.redox.2016.12.035Chandimali N, Bak SG, Park EH, Lim HJ, Won YS, Kim EK, et al. Free radicals and their impact on health and antioxidant defenses: a review. Cell Death Discovery. 2025;11(1):19. https://doi.org/10.1038/s41420-024-02278-8Chandimali N, Bak SG, Park EH, Lim HJ, Won YS, Kim EK, et al. Free radicals and their impact on health and antioxidant defenses: a review. Cell Death Discovery. 2025;11(1):19. https://doi.org/10.1038/s41420-024-02278-8Baker A, Lin CC, Lett C, Karpinska B, Wright MH, Foyer CH. Catalase: A critical node in the regulation of cell fate. Free Radical Biology and Medicine. 2023;199:56–66. https://doi.org/10.1016/j.freeradbiomed.2023.02.009Baker A, Lin CC, Lett C, Karpinska B, Wright MH, Foyer CH. Catalase: A critical node in the regulation of cell fate. Free Radical Biology and Medicine. 2023;199:56–66. https://doi.org/10.1016/j.freeradbiomed.2023.02.009Ren X, Zou L, Zhang X, Branco V, Wang J, Carvalho C, et al. Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxidants & Redox Signaling. 2017;27(13):989–1010. https://doi.org/10.1089/ars.2016.6925Ren X, Zou L, Zhang X, Branco V, Wang J, Carvalho C, et al. Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxidants & Redox Signaling. 2017;27(13):989–1010. https://doi.org/10.1089/ars.2016.6925Kennedy L, Sandhu JK, Harper ME, Cuperlovic-Culf M. Role of Glutathione in Cancer: From Mechanisms to Therapies. Biomolecules. 2020;10(10):1429. https://doi.org/10.3390/biom10101429Kennedy L, Sandhu JK, Harper ME, Cuperlovic-Culf M. Role of Glutathione in Cancer: From Mechanisms to Therapies. Biomolecules. 2020;10(10):1429. https://doi.org/10.3390/biom10101429Østergaard H, Tachibana C, Winther JR. Monitoring disulfide bond formation in the eukaryotic cytosol. Journal of Cell Biology. 2004;166(3):337–45. https://doi.org/10.1083/jcb.200402120Østergaard H, Tachibana C, Winther JR. Monitoring disulfide bond formation in the eukaryotic cytosol. Journal of Cell Biology. 2004;166(3):337–45. https://doi.org/10.1083/jcb.200402120Ogata FT, Branco V, Vale FF, Coppo L. Glutaredoxin: Discovery, redox defense and much more. Redox Biology. 2021;43:101975. https://doi.org/10.1016/j.redox.2021.101975Ogata FT, Branco V, Vale FF, Coppo L. Glutaredoxin: Discovery, redox defense and much more. Redox Biology. 2021;43:101975. https://doi.org/10.1016/j.redox.2021.101975Perkins A, Nelson KJ, Parsonage D, Poole LB, Karplus PA. Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling. Trends in Biochemical Sciences. 2015;40(8):435–45. https://doi.org/10.1016/j.tibs.2015.05.001Perkins A, Nelson KJ, Parsonage D, Poole LB, Karplus PA. Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling. Trends in Biochemical Sciences. 2015;40(8):435–45. https://doi.org/10.1016/j.tibs.2015.05.001Purohit V, Simeone DM, Lyssiotis CA. Metabolic Regulation of Redox Balance in Cancer. Cancers. 2019;11(7):955. https://doi.org/10.3390/cancers11070955Purohit V, Simeone DM, Lyssiotis CA. Metabolic Regulation of Redox Balance in Cancer. Cancers. 2019;11(7):955. https://doi.org/10.3390/cancers11070955Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative Stress in Cancer. Cancer Cell. 2020;38(2):167–97. https://doi.org/10.1016/j.ccell.2020.06.001Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative Stress in Cancer. Cancer Cell. 2020;38(2):167–97. https://doi.org/10.1016/j.ccell.2020.06.001Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiological Reviews. 2018;98(3):1169–203. https://doi.org/10.1152/physrev.00023.2017Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiological Reviews. 2018;98(3):1169–203. https://doi.org/10.1152/physrev.00023.2017Campos-Sandoval JA, Gómez-García MC, de los Santos-Jiménez J, Matés JM, Alonso FJ, Márquez J. Antioxidant responses related to temozolomide resistance in glioblastoma. Neurochemistry International. 2021;149:105136. https://doi.org/10.1016/j.neuint.2021.105136Campos-Sandoval JA, Gómez-García MC, de los Santos-Jiménez J, Matés JM, Alonso FJ, Márquez J. Antioxidant responses related to temozolomide resistance in glioblastoma. Neurochemistry International. 2021;149:105136. https://doi.org/10.1016/j.neuint.2021.105136Cong ZX, Wang HD, Zhou Y, Wang JW, Pan H, Zhang DD, et al. Temozolomide and irradiation combined treatment-induced Nrf2 activation increases chemoradiation sensitivity in human glioblastoma cells. Journal of Neuro-Oncology. 2014;116(1):41–8. https://doi.org/10.1007/s11060-013-1260-xCong ZX, Wang HD, Zhou Y, Wang JW, Pan H, Zhang DD, et al. Temozolomide and irradiation combined treatment-induced Nrf2 activation increases chemoradiation sensitivity in human glioblastoma cells. Journal of Neuro-Oncology. 2014;116(1):41–8. https://doi.org/10.1007/s11060-013-1260-xRocha CRR, Rocha AR, Silva MM, Gomes LR, Latancia MT, Andrade-Tomaz M, et al. Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries. Cells. 2020;9(12):2573. https://doi.org/10.3390/cells9122573Rocha CRR, Rocha AR, Silva MM, Gomes LR, Latancia MT, Andrade-Tomaz M, et al. Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries. Cells. 2020;9(12):2573. https://doi.org/10.3390/cells9122573Singer E, Judkins J, Salomonis N, Matlaf L, Soteropoulos P, McAllister S, et al. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death & Disease. 2015;6(1):e1601. https://doi.org/10.1038/cddis.2014.566Singer E, Judkins J, Salomonis N, Matlaf L, Soteropoulos P, McAllister S, et al. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death & Disease. 2015;6(1):e1601. https://doi.org/10.1038/cddis.2014.566Zhu Z, Du S, Du Y, Ren J, Ying G, Yan Z. Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis. Journal of Neurochemistry. 2018;144(1):93–104. https://doi.org/10.1111/jnc.14250Zhu Z, Du S, Du Y, Ren J, Ying G, Yan Z. Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis. Journal of Neurochemistry. 2018;144(1):93–104. https://doi.org/10.1111/jnc.14250Yao A, Storr SJ, Al-hadyan K, Rahman R, Smith S, Grundy R, et al. Thioredoxin System Protein Expression Is Associated with Poor Clinical Outcome in Adult and Paediatric Gliomas and Medulloblastomas. Molecular Neurobiology. 2020;57(7):2889–901. https://doi.org/10.1007/s12035-020-01928-zYao A, Storr SJ, Al-hadyan K, Rahman R, Smith S, Grundy R, et al. Thioredoxin System Protein Expression Is Associated with Poor Clinical Outcome in Adult and Paediatric Gliomas and Medulloblastomas. Molecular Neurobiology. 2020;57(7):2889–901. https://doi.org/10.1007/s12035-020-01928-zHaas B, Schütte L, Wos-Maganga M, Weickhardt S, Timmer M, Eckstein N. Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. International Journal of Molecular Sciences. 2018;19(10):2874. https://doi.org/10.3390/ijms19102874Haas B, Schütte L, Wos-Maganga M, Weickhardt S, Timmer M, Eckstein N. Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. International Journal of Molecular Sciences. 2018;19(10):2874. https://doi.org/10.3390/ijms19102874Oliva CR, Moellering DR, Gillespie GY, Griguer CE. Acquisition of Chemoresistance in Gliomas Is Associated with Increased Mitochondrial Coupling and Decreased ROS Production. PLOS One. 2011;6(9):e24665. https://doi.org/10.1371/journal.pone.0024665Oliva CR, Moellering DR, Gillespie GY, Griguer CE. Acquisition of Chemoresistance in Gliomas Is Associated with Increased Mitochondrial Coupling and Decreased ROS Production. PLOS One. 2011;6(9):e24665. https://doi.org/10.1371/journal.pone.0024665Chang KY, Hsu TI, Hsu CC, Tsai SY, Liu JJ, Chou SW, et al. Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O 6 -methylguanine-DNA methyltransferase. Redox Biology. 2017;13:655–64. https://doi.org/10.1016/j.redox.2017.08.005Chang KY, Hsu TI, Hsu CC, Tsai SY, Liu JJ, Chou SW, et al. Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O 6 -methylguanine-DNA methyltransferase. Redox Biology. 2017;13:655–64. https://doi.org/10.1016/j.redox.2017.08.005Rasper M, Schäfer A, Piontek G, Teufel J, Brockhoff G, Ringel F, et al. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro-Oncology. 2010;12(10):1024–33. https://doi.org/10.1093/neuonc/noq070Rasper M, Schäfer A, Piontek G, Teufel J, Brockhoff G, Ringel F, et al. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro-Oncology. 2010;12(10):1024–33. https://doi.org/10.1093/neuonc/noq070Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proceedings of the National Academy of Sciences. 2013;110(21):8644–9. https://doi.org/10.1073/pnas.1221478110Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proceedings of the National Academy of Sciences. 2013;110(21):8644–9. https://doi.org/10.1073/pnas.1221478110Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell. 2012;149(5):1060–72. https://doi.org/10.1016/j.cell.2012.03.042Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell. 2012;149(5):1060–72. https://doi.org/10.1016/j.cell.2012.03.042Rocha CRR, Garcia CCM, Vieira DB, Quinet A, de Andrade-Lima LC, Munford V, et al. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo. Cell Death & Disease. 2014;5(10):e1505. https://doi.org/10.1038/cddis.2014.465Rocha CRR, Garcia CCM, Vieira DB, Quinet A, de Andrade-Lima LC, Munford V, et al. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo. Cell Death & Disease. 2014;5(10):e1505. https://doi.org/10.1038/cddis.2014.465Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A, et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer. 2009;9(1):372. https://doi.org/10.1186/1471-2407-9-372Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A, et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer. 2009;9(1):372. https://doi.org/10.1186/1471-2407-9-372Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447(7146):865–9. https://doi.org/10.1038/nature05859Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447(7146):865–9. https://doi.org/10.1038/nature05859Chen L, Li X, Liu L, Yu B, Xue Y, Liu Y. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncology Reports. 2015;33(3):1465–74. https://doi.org/10.3892/or.2015.3712Chen L, Li X, Liu L, Yu B, Xue Y, Liu Y. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncology Reports. 2015;33(3):1465–74. https://doi.org/10.3892/or.2015.3712Yang FC, Wang C, Zhu J, Gai QJ, Mao M, He J, et al. Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain. Laboratory Investigation. 2022;102(7):741–52. https://doi.org/10.1038/s41374-022-00779-7Yang FC, Wang C, Zhu J, Gai QJ, Mao M, He J, et al. Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain. Laboratory Investigation. 2022;102(7):741–52. https://doi.org/10.1038/s41374-022-00779-7Chmelyuk N, Kordyukova M, Sorokina M, Sinyavskiy S, Meshcheryakova V, Belousov V, et al. Inhibition of Thioredoxin-Reductase by Auranofin as a Pro-Oxidant Anticancer Strategy for Glioblastoma: In Vitro and In Vivo Studies. International Journal of Molecular Sciences. 2025;26(5):2084. https://doi.org/10.3390/ijms26052084Chmelyuk N, Kordyukova M, Sorokina M, Sinyavskiy S, Meshcheryakova V, Belousov V, et al. Inhibition of Thioredoxin-Reductase by Auranofin as a Pro-Oxidant Anticancer Strategy for Glioblastoma: In Vitro and In Vivo Studies. International Journal of Molecular Sciences. 2025;26(5):2084. https://doi.org/10.3390/ijms26052084Jamali F, Lan K, Daniel P, Petrecca K, Sabri S, Abdulkarim B. Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells. Antioxidants. 2024;13(10):1201. https://doi.org/10.3390/antiox13101201Jamali F, Lan K, Daniel P, Petrecca K, Sabri S, Abdulkarim B. Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells. Antioxidants. 2024;13(10):1201. https://doi.org/10.3390/antiox13101201Martinez-Jaramillo E, Jamali F, Abdalbari FH, Abdulkarim B, Jean-Claude BJ, Telleria CM, et al. Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression. Cancers. 2024;16(13):2319. https://doi.org/10.3390/cancers16132319Martinez-Jaramillo E, Jamali F, Abdalbari FH, Abdulkarim B, Jean-Claude BJ, Telleria CM, et al. Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression. Cancers. 2024;16(13):2319. https://doi.org/10.3390/cancers16132319Kumthekar P, Grimm S, Chandler J, Mehta M, Marymont M, Levy R, et al. A phase II trial of arsenic trioxide and temozolomide in combination with radiation therapy for patients with malignant gliomas. Journal of Neuro-Oncology. 2017;133(3):589–94. https://doi.org/10.1007/s11060-017-2469-xKumthekar P, Grimm S, Chandler J, Mehta M, Marymont M, Levy R, et al. A phase II trial of arsenic trioxide and temozolomide in combination with radiation therapy for patients with malignant gliomas. Journal of Neuro-Oncology. 2017;133(3):589–94. https://doi.org/10.1007/s11060-017-2469-xAllen BG, Bodeker KL, Smith MC, Monga V, Sandhu S, Hohl R, et al. First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clinical Cancer Research. 2019;25(22):6590–7. https://doi.org/10.1158/1078-0432.CCR-19-0594Allen BG, Bodeker KL, Smith MC, Monga V, Sandhu S, Hohl R, et al. First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clinical Cancer Research. 2019;25(22):6590–7. https://doi.org/10.1158/1078-0432.CCR-19-0594Yuan Y, Xue X, Guo RB, Sun XL, Hu G. Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway. CNS Neuroscience & Therapeutics. 2012;18(7):536–46. https://doi.org/10.1111/j.1755-5949.2012.00319.xYuan Y, Xue X, Guo RB, Sun XL, Hu G. Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway. CNS Neuroscience & Therapeutics. 2012;18(7):536–46. https://doi.org/10.1111/j.1755-5949.2012.00319.xZhang K, Chen D, Ma K, Wu X, Hao H, Jiang S. NAD(P) H:Quinone Oxidoreductase 1 (NQO1) as a Therapeutic and Diagnostic Target in Cancer. Journal of Medicinal Chemistry. 2018;61(16):6983–7003. https://doi.org/10.1021/acs.jmedchem.8b00124Zhang K, Chen D, Ma K, Wu X, Hao H, Jiang S. NAD(P) H:Quinone Oxidoreductase 1 (NQO1) as a Therapeutic and Diagnostic Target in Cancer. Journal of Medicinal Chemistry. 2018;61(16):6983–7003. https://doi.org/10.1021/acs.jmedchem.8b00124Zhong B, Yu J, Hou Y, Ai N, Ge W, Lu JJ, et al. A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis. Free Radical Biology and Medicine. 2021;166:104–15. https://doi.org/10.1016/j.freeradbiomed.2021.02.014Zhong B, Yu J, Hou Y, Ai N, Ge W, Lu JJ, et al. A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis. Free Radical Biology and Medicine. 2021;166:104–15. https://doi.org/10.1016/j.freeradbiomed.2021.02.014Dai Y, Min Y, Zhou L, Cheng L, Ni H, Yang Y, et al. Braintargeting redox-sensitive micelles for codelivery of TMZ and β-lapachone for glioblastoma therapy. Nanomedicine: Nanotechnology, Biology and Medicine. 2024;61:102772. https://doi.org/10.1016/j.nano.2024.102772Dai Y, Min Y, Zhou L, Cheng L, Ni H, Yang Y, et al. Braintargeting redox-sensitive micelles for codelivery of TMZ and β-lapachone for glioblastoma therapy. Nanomedicine: Nanotechnology, Biology and Medicine. 2024;61:102772. https://doi.org/10.1016/j.nano.2024.102772Ren X, Santhosh SM, Coppo L, Ogata FT, Lu J, Holmgren A. The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress. Free Radical Biology and Medicine. 2019;134:350–8. https://doi.org/10.1016/j.freeradbiomed.2019.01.037Ren X, Santhosh SM, Coppo L, Ogata FT, Lu J, Holmgren A. The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress. Free Radical Biology and Medicine. 2019;134:350–8. https://doi.org/10.1016/j.freeradbiomed.2019.01.037Sumiyoshi A, Shibata S, Lazarova D, Zhelev Z, Aoki I, Bakalova R. Tolerable treatment of glioblastoma with redox-cycling ‘mitocans’: a comparative study in vivo. Redox Report: Communications in Free Radical Research. 2023;28(1):2220531. https://doi.org/10.1080/13510002.2023.2220531Sumiyoshi A, Shibata S, Lazarova D, Zhelev Z, Aoki I, Bakalova R. Tolerable treatment of glioblastoma with redox-cycling ‘mitocans’: a comparative study in vivo. Redox Report: Communications in Free Radical Research. 2023;28(1):2220531. https://doi.org/10.1080/13510002.2023.2220531Pires V, Bramatti I, Aschner M, Branco V, Carvalho C. Thioredoxin Reductase Inhibitors as Potential Antitumors: Mercury Compounds Efficacy in Glioma Cells. Frontiers in Molecular Biosciences. 2022;9:889971. https://doi.org/10.3389/fmolb.2022.889971Pires V, Bramatti I, Aschner M, Branco V, Carvalho C. Thioredoxin Reductase Inhibitors as Potential Antitumors: Mercury Compounds Efficacy in Glioma Cells. Frontiers in Molecular Biosciences. 2022;9:889971. https://doi.org/10.3389/fmolb.2022.889971Wei D, Zhang N, Qu S, Wang H, Li J. Advances in nanotechnology for the treatment of GBM. Frontiers in Neuroscience. 2023;17:1180943. https://doi.org/10.3389/fnins.2023.1180943Wei D, Zhang N, Qu S, Wang H, Li J. Advances in nanotechnology for the treatment of GBM. Frontiers in Neuroscience. 2023;17:1180943. https://doi.org/10.3389/fnins.2023.1180943Cui Y, Xu Q, Chow PKH, Wang D, Wang CH. Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment. Biomaterials. 2013;34(33):8511–20. https://doi.org/10.1016/j.biomaterials.2013.07.075Cui Y, Xu Q, Chow PKH, Wang D, Wang CH. Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment. Biomaterials. 2013;34(33):8511–20. https://doi.org/10.1016/j.biomaterials.2013.07.075Chaiswing L, St Clair WH, St Clair DK. Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer. Antioxidants & Redox Signaling. 2018;29(13):1237–72. https://doi.org/10.1089/ars.2017.7485Chaiswing L, St Clair WH, St Clair DK. Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer. Antioxidants & Redox Signaling. 2018;29(13):1237–72. https://doi.org/10.1089/ars.2017.7485de Souza I, Monteiro LKS, Guedes CB, Silva MM, Andrade-Tomaz M, Contieri B, et al. High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation. Cell Death & Disease. 2022;13(7):591. https://doi.org/10.1038/s41419-022-05044-9de Souza I, Monteiro LKS, Guedes CB, Silva MM, Andrade-Tomaz M, Contieri B, et al. High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation. Cell Death & Disease. 2022;13(7):591. https://doi.org/10.1038/s41419-022-05044-9Morgenstern C, Lastres-Becker I, Demirdöğen BC, Costa VM, Daiber A, Foresti R, et al. Biomarkers of NRF2 signalling: Current status and future challenges. Redox Biology. 2024;72:103134. https://doi.org/10.1016/j.redox.2024.103134Morgenstern C, Lastres-Becker I, Demirdöğen BC, Costa VM, Daiber A, Foresti R, et al. Biomarkers of NRF2 signalling: Current status and future challenges. Redox Biology. 2024;72:103134. https://doi.org/10.1016/j.redox.2024.103134Kim Y, Ju H, Yoo SY, Jeong J, Heo J, Lee S, et al. Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer. Cell Reports Medicine. 2023;4(10):101224. https://doi.org/10.1016/j.xcrm.2023.101224Kim Y, Ju H, Yoo SY, Jeong J, Heo J, Lee S, et al. Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer. Cell Reports Medicine. 2023;4(10):101224. https://doi.org/10.1016/j.xcrm.2023.101224Deng Z, Luo J, Ma J, Jin YN, Yu YV. Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma. Aging. 2024;16(11):9518–46. https://doi.org/10.18632/aging.205881Deng Z, Luo J, Ma J, Jin YN, Yu YV. Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma. Aging. 2024;16(11):9518–46. https://doi.org/10.18632/aging.205881Chełchowska M, Gajewska J, Szczepanik E, Mazur J, Cychol A, Kuźniar-Pałka A, et al. Oxidative Stress Indicated by Nuclear Transcription Factor Nrf2 and Glutathione Status in the Blood of Young Children with Autism Spectrum Disorder: Pilot Study. Antioxidants. 2025;14(3):320. https://doi.org/10.3390/antiox14030320Chełchowska M, Gajewska J, Szczepanik E, Mazur J, Cychol A, Kuźniar-Pałka A, et al. Oxidative Stress Indicated by Nuclear Transcription Factor Nrf2 and Glutathione Status in the Blood of Young Children with Autism Spectrum Disorder: Pilot Study. Antioxidants. 2025;14(3):320. https://doi.org/10.3390/antiox14030320

The authors declare that there are no conflicts of interest present.