Oncotarget

Research Papers:

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

Tina Sehm _, Zheng Fan, Ali Ghoochani, Manfred Rauh, Tobias Engelhorn, Georgia Minakaki, Arnd Dörfler, Jochen Klucken, Michael Buchfelder, Ilker Y. Eyüpoglu and Nicolai Savaskan

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Oncotarget. 2016; 7:36021-36033. https://doi.org/10.18632/oncotarget.8651

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Abstract

Tina Sehm1, Zheng Fan1, Ali Ghoochani1, Manfred Rauh2, Tobias Engelhorn3, Georgia Minakaki4,, Arnd Dörfler3, Jochen Klucken4,, Michael Buchfelder1, Ilker Y. Eyüpoglu1,*, Nicolai Savaskan1,5,*

1Translational 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

2Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany

3Department of Neuroradiology, Schwabachanlage 6 (Kopfklinik), Universitätsklinikum Erlangen (UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany

4Department of Molecular Neurology, Universitätsklinikum Erlangen(UKER), Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany

5BiMECON Ent., Berlin, Germany

*Both authors contribute as senior leader to this work

Correspondence to:

Nicolai Savaskan, e-mail: [email protected]; [email protected]

Keywords: glioblastoma, cancer, tumor microenvironment, brain swelling

Received: December 22, 2015    Accepted: March 28, 2016    Published: April 08, 2016

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.


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