Journal of Clinical PracticeJournal of Clinical PracticeКлиническая практика2220-30952618-8627Eco-Vector11478710.17816/clinpract114787ReviewsНаучные обзорыReview ArticleFerroptosis in the pathogenesis of brain tumorsФерроптоз в патогенезе опухолей головного мозгаhttps://orcid.org/0000-0001-6607-430X8417-3876NikolaevAlexandr A.НиколаевАлександр Аркадьевич
Russian Federation

MD, PhD, Professor

д.м.н., профессор

chimnik@mail.ruhttps://orcid.org/0000-0003-0458-07036098-1321BelopasovVladimir V.БелопасовВладимир Викторович
Russian Federation

MD, PhD, Professor

д.м.н., профессор

belopasov@yandex.ruAstrakhan State Medical UniversityАстраханский государственный медицинский университет291220222401202313468732211202204122022Copyright ©; 2023, Eco-VectorCopyright ©; 2023, Эко-Вектор2023Eco-VectorЭко-Векторhttps://creativecommons.org/licenses/by-nc-nd/4.0https://clinpractice.ru/clinpractice/article/view/114787

The field of research on ferroptosis has seen an explosive growth in the past few years since the term was coined in 2012. This review highlights the current state of knowledge on the developmental mechanism of this unique mode of cell death, induced by iron-dependent phospholipid peroxidation, which is regulated by a variety of cellular metabolic events, including redox homeostasis. The xCT system, an amino acid antiporter that supports the synthesis of glutathione (GSH) and oxidation protection, is among these factors. The risk of iron accumulation in neurons, astrocytes, oligodendrocytes, microglia, and Schwann cells and the development of oxidative stress are discussed. Ferroptosis triggers a cascade of events including activation of inflammation, oxidation of neurotransmitters, impaired neuronal communication, myelin sheath degeneration, astrocyte dysregulation, dementia, and cell death. On the other hand, the exceptional vulnerability of cancer cells originating from the nervous tissue to ferroptosis is estimated. The evidence is given for the initiation of ferroptosis in tumor cells as a factor inhibiting the growth and promoting the death of these cells. Particular attention is paid to the pharmacological modulation of ferroptosis through its induction and inhibition for the treatment of drug-resistant cancers. The choice of targets for the induction of ferroptosis in cancer cells is discussed. Glutathione peroxidase 4 and xCT amino acid antiporter are recognized as the most preferred targets and the antitumor potential of their inhibition and side effects are evaluated.

Область исследований ферроптоза в последние несколько лет демонстрирует взрывной рост, с тех пор как этот термин был предложен в 2012 году. В данном обзоре освещается современное состояние знаний о механизме развития этого уникального способа гибели клеток, вызванного железозависимым перекисным окислением фосфолипидов, который регулируется множеством клеточных метаболических событий, включая окислительно-восстановительный гомеостаз. Среди этих факторов система xCT — аминокислотный антипортер, который поддерживает синтез глутатиона (GSH) и окислительную защиту. Обсуждается опасность не только накопления железа в нейронах, астроцитах, олигодендроцитах, микроглии и шванновских клетках, но и развития окислительного стресса. Ферроптоз запускает каскад событий, включая активацию воспаления, окисление нейротрансмиттеров, нарушение нейронных связей, дегенерацию миелиновой оболочки, дисрегуляцию астроцитов, деменцию и гибель клеток. С другой стороны, оценивается исключительная уязвимость для ферроптоза опухолевых клеток, ведущих происхождение из нервной ткани. Приводятся доказательства инициации ферроптоза в опухолевых клетках как фактора торможения роста и гибели этих клеток. Особое внимание уделено фармакологической модуляция ферроптоза путем его индукции и ингибирования для лечения лекарственно-устойчивых видов рака. Обсуждается выбор мишеней для индукции ферроптоза в раковых клетках. Глутатионпероксидаза 4 и аминокислотный антипортер xCT признаны наиболее предпочтительными мишенями; оцениваются антиопухолевый потенциал их ингибирования и побочные эффекты.

brain tumorsferroptosisglutathione peroxidase 4lipid peroxidationопухоли мозгаферроптозглутатионпероксидаза 4перекисное окисление липидовФГБОУ ВО «Астраханский ГМУ» Минздрава РоссииAstrakhan State Medical University of the Ministry of Health of RussiaLouis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol. 2021;23(8):1231–1251. doi: 10.1093/neuonc/noab106Wirsching HG, Galanis E, Weller M. Glioblastoma. Handb Clin Neurol. 2016;134:381–397. doi: 10.1016/B978-0-12-802997-8.00023-2Nakagawara A, Li Y, Izumi H, et al. Neuroblastoma. Jpn J Clin Oncol. 2018;48(3):214–241. doi: 10.1093/jjco/hyx176Klekner L, Szivos L, Virga J, et al. Significance of liquid biopsyin glioblastoma: A review. J Biotechnol. 2019;298:82–87. doi: 10.1016/j.jbiotec.2019.04.011Sathornsumetee S, Rich JN. New approaches to primary brain tumor treatment. Anticancer Drugs. 2006;17(9):1003–1016. doi: 10.1097/01.cad.0000231473.00030.1fQiu Y. The relation between necessary trace element iron and various diseases. Biol Trace Elem Res. 1999;4:19–22. doi: 10.16755/j.cnki.issn.1006-446x.1997.10.006Agrawal KN. Iron Brain. J Univers Coll Med Sci. 2013;1:1–6. doi: 10.3126/jucms.v1i1.8425Mccann S, Amado M, Moore SE. The role of iron in brain development: A systematic review. Nutrients. 2020;12(7): 2001–2023. doi: 10.3390/nu12072001Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology, and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266–282. doi: 10.1038/s41580-020-00324-8Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2(8): 406–414. doi: 10.1038/nchembio807Montalbetti N, Simonin A, Kovacs G, Hediger MA. Mammalian iron transporters: Families SLC11 and SLC40. Mol Aspects Med. 2013;34(2-3):270–287. doi: 10.1016/j.mam.2013.01.002DeGregorio-Rocasolano N, Martí-Sistac O, Gasull T. Deciphering the iron side of stroke: neurodegeneration at the crossroads between iron dyshomeostasis, excitotoxicity, and ferroptosis. Front Neurosci. 2019;13(1):85–96. doi: 10.3389/fnins.2019.00085Reichert CO, de Freitas FA, Sampaio-Silva J, et al. Ferroptosis mechanisms involvel in neurodegenerative diseases. Int J Mol Sci. 2020;21(22):8765–8783. doi: 10.3390/ijms21228765Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi: 10.1016/j.cell.2012.03.042Bayır H, Anthonymuthu TS, Tyurina YY, et al. Achieving life through death: redox biology of lipid peroxidation in ferroptosis. Cell Chem. Biol. 2020;27(4):387–408. doi: 10.1016/j.chembiol.2020.03.014Fricker M, Tolkovsky AM, Borutaite V, Coleman M. Neuronal cell death. Physiol Rev. 2018;98(2):813–880. doi: 10.1152/physrev.00011.2017Sun Y, Chen P, Zhai B, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108. doi: 10.1016/j.biopha.2020.110108Galaris D, Barbouti A, Pantopoulos K. Iron homeostasis and oxidative stress: an intimate relationship. Biochim Biophys Acta Mol Cell Res. 2019;1866(12):118535–118548 doi: 10.1016/j.bbamcr.2019.118535Mao H, Zhao Y, Li H, Lei L. Ferroptosis as an emerging target in inflammatory diseases. Prog Biophys Mol Biol. 2020;155:20–28. doi: 10.1016/j.pbiomolbio.2020.04.001Lachaier E, Louandre C, Godin C, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 2014;34(11):6417–6422.Kabiraj P, Valenzuela CA, Marin JE, et al. The neuroprotective role of ferrostatin-1 under rotenoneinduced oxidative stress in dopaminergic neuroblastoma cells. Protein J. 2015;34(5): 349–358. doi: 10.1007/s10930-015-9629-7Wang YQ, Chang SY, Wu Q, et al. The protective role of mitochondrial ferritin on erastin-induced ferroptosis. Front Aging Neurosci. 2016;8:308. doi: 10.3389/fnagi.2016.00308Ivanov SD, Semenov AL, Mikhelson VM, et al. Effects of iron ion additional introduction in radiation therapy of tumor-bearing animals. Radiats Biol Radioecol. 2013;53(3):296–303 doi: 10.7868/s0869803113030065Ivanov SD, Semenov AL, Kovanko EG, Yamshanov VA. Effects of iron ions and iron chelation on the efficiency of experimental radiotherapy of animals with gliomas. Bull Exp Biol Med. 2015;158(6):800–803. doi: 10.1007/s10517-015-2865-1Chen D, Rauh M, Buchfelder M, Savaskan N. The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas. Oncotarget. 2017;8(31):51164–51176. doi: 10.18632/oncotarget.17737Sehm T, Rauh M, Wiendieck K, et al. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis. Oncotarget. 2017;7(46):74630–74647. doi: 10.18632/oncotarget.11858Chung WJ, Sontheimer H. Sulfasalazine inhibits the growth of primary brain tumorsindependent of nuclear factor-kappa B. J Neurochem. 2009;110(1):182–193. doi: 10.1111/j.1471-4159.2009.06129.xSehm T, Fan Z, Ghoochani A, et al. Sulfasalazine impacts on ferroptotic cell deathand alleviates the tumor microenvironment and glioma-induced brain edema. Oncotarget. 2016;7(24): 36021–36033. doi: 10.18632/oncotarget.8651Hare D, Ayton S, Bush A, Lei P. A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci. 2013;5:34. doi: 10.3389/fnagi.2013.00034Dias V, Junn E, Mouradian MM. The role of oxidative stress in parkinsons disease. J Parkinson Dis. 2013;3(4):461–491. doi: 10.3233/JPD-130230Fan Z, Wirth AK, Chen D, et al. Nrf2-Keap1pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017; 6(8):371–385. doi: 10.1038/oncsis.2017.65Ye P, Mimura J, Okada T, et al. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol Cell Biol. 2014;34(18):3421–3434. doi: 10.1128/MCB.00221-14Habib E, Linher-Melville K, Lin HX, Singh G. Expression of xCT and activity of systemxc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress. Redox Biol. 2015;5:33–42. doi: 10.1016/j.redox.2015.03.003Hassannia B, Wiernicki B, Ingold I, et al. Nano-targeted induction of dual ferroptotic mechanismseradicates high-risk neuroblastoma. J Clin Invest. 2018;128(8):3341–3355. doi: 10.1172/JCI99032Abdalkader M, Lampinen R, Kanninen KM, Malm TM. Targeting Nrf2 to suppress ferroptosis and mitochondrial dysfunction in neurodegeneration. Front Neurosci. 2018;12:466–481. doi: 10.3389/fnins.2018.00466Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830–849. doi: 10.1016/j.ccell.2019.04.002Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1-2): 317–331. doi: 10.1016/j.cell.2013.12.010Chen Y, Liu Y T, et al. Quantitative profiling of protein carbonylations in ferroptosis by an aniline-derived probe. J Am Chem Soc. 2018;140(13):4712–4720. doi: 10.1021/jacs.8b01462Eaton JK, Ruberto RA, Kramm A, et al. Diacylfuroxans are masked nitrile oxides that inhibit GPX4 covalently. J Am Chem Soc. 2019;141(51):20407–20415. doi: 10.1021/jacs.9b10769Eaton JK, LR, Ruberto RA, et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat Chem Biol. 2020;16(5):497–506. doi: 10.1038/s41589-020-0501-5Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol. 2019;15(12):1137–1147. doi: 10.1038/s41589-019-0408-1Weiland A, Wang Y, Wu W, et al. J Mol Neurobiol. 2019;56(7): 4880–4893. doi: 10.1007/s12035-018-1403-3Sato H AM, Kimata M, et al. Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem. 2005;280(45): 37423–37429. doi: 10.1074/jbc.M506439200Robert MS, Buckingham S, Campbell S, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015;7(289):289ra286. doi: 10.1126/scitranslmed.aaa8103Zhang Y, Tan HJ, Daniels J, et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem Biol. 2019;26(5):623–633e629. doi: 10.1016/j.chembiol.2019.01.008Badgley MA, Kremer DM, Maurer HC, et al. Cysteine. Science. 2020;368(6486):85–89. doi: 10.1126/science.aaw 9872Sato M, Onuma K, Mio D, et al. Loss of the cystine/glutamate antiporter in melanoma abrogates tumor metastasis and markedly increases survival rates of mice. Int J Cancer. 2020; 147(11):3224–3235. doi: 10.1002/ijc.33262Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–698. doi: 10.1038/s41586-019-1707-0Sano H, Futamura M, Gaowa S, et al. p53/Mieap-regulated mitochondrial quality control plays an important role as a tumor suppressor in gastric and esophageal cancers. Biochem Biophys Res Commun. 2020;529(3):582–589. doi: 10.1016/j.bbrc.2020.05.168Liu Y, Gu W. p53 in ferroptosis regulation: The new weapon for the old guardian. Cell Death Differ. 2022;29(5):895–910. doi: 10.1038/s41418-022-00943-yDoll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–698. doi: 10.1038/s41586-019-1707-0 2019Yuan B, Zhao XD, Shen JD, et al. Activation of SIRT1 alleviates ferroptosis in the early brain injury after subarachnoid hemorrhage. Oxid Med Cell Longev. 2022;2022:9069825. doi: 10.1155/2022/9069825