Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

dc.contributor.authorSehm, Tina
dc.contributor.authorFan, Zheng
dc.contributor.authorGhoochani, Ali
dc.contributor.authorRauh, Manfred
dc.contributor.authorEngelhorn, Tobias
dc.contributor.authorMinakaki, Georgia
dc.contributor.authorDörfler, Arnd
dc.contributor.authorKlucken, Jochen
dc.contributor.authorBuchfelder, Michael
dc.contributor.authorEyüpoglu, Ilker Y.
dc.contributor.authorSavaskan, Nicolai
dc.date.accessioned2017-10-09
dc.date.available2017-09-27
dc.date.created2016
dc.date.issued2017-10-09
dc.description.abstractThe glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 µM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor.en
dc.identifier.citationOncotarget 7.24 (2016). <http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=8651&path[]=25909>
dc.identifier.doihttps://doi.org/10.18632/oncotarget.8651
dc.identifier.opus-id8787
dc.identifier.urihttps://open.fau.de/handle/openfau/8787
dc.identifier.urnurn:nbn:de:bvb:29-opus4-87876
dc.language.isoen
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/de/deed.de
dc.subjectglioblastoma
dc.subjectcancer
dc.subjecttumor microenvironment
dc.subjectbrain swelling
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleSulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edemaen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.journal.issue24
local.journal.titleOncotarget
local.journal.volume7
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.gnd-
local.subject.sammlungUniversität Erlangen-Nürnberg / Von der FAU geförderte Open Access Artikel / Von der FAU geförderte Open Access Artikel 2016
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