title: Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema.
abstract: The 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.
authors.affiliation: Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Sehm
authors.affiliation: Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Ghoochani
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.affiliation: Department of Neuroradiology, Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engelhorn
authors.affiliation: Department of Molecular Neurology, Universitätsklinikum Erlangen(UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Minakaki
authors.affiliation: Department of Neuroradiology, Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
authors.forename: Arnd
authors.initials: A
authors.lastname: Dörfler
authors.affiliation: Department of Molecular Neurology, Universitätsklinikum Erlangen(UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Klucken
authors.affiliation: Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors.forename: Ilker Y
authors.initials: IY
authors.lastname: Eyüpoglu
authors.affiliation: Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.|BiMECON Ent., Berlin, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Savaskan
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005910:Glioma / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D017208:Rats, Wistar; D012460:Sulfasalazine / Q000494:pharmacology*; D000077204:Temozolomide; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D027322:Amino Acid Transport System X-AG; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012460:Sulfasalazine; D003606:Dacarbazine; D000077204:Temozolomide
keywords: brain swelling; cancer; glioblastoma; tumor microenvironment