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

Sehm T, Fan Z, Ghoochani A, Rauh M, Engelhorn T, Minakaki G, Dörfler A, Klucken J, Buchfelder M, Eyüpoglu IY, Savaskan N (2016)

Publication Status: Published

Publication Type: Journal article

Publication year: 2016

Journal

Oncotarget Impact Journals

Book Volume: 7

Pages Range: 36021-36033

Journal Issue: 24

DOI: 10.18632/oncotarget.8651

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 with CRIS profile

Tina Sehm Department of Neurosurgery Zheng Fan Department of Neurosurgery Ali Ghoochani Department of Neurosurgery Manfred Rauh Medizinische Fakultät Tobias Martin Engelhorn Department of Neuroradiology Georgia Minakaki Professur für Molekulare Neurologie Arnd Dörfler Department of Neuroradiology Jochen Klucken Department of Molecular Neurology Michael Buchfelder Lehrstuhl für Neurochirurgie Ilker Yasin Eyüpoglu Medizinische Fakultät

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

How to cite

APA:

Sehm, T., Fan, Z., Ghoochani, A., Rauh, M., Engelhorn, T., Minakaki, G.,... Savaskan, N. (2016). Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema. Oncotarget, 7(24), 36021-36033. https://doi.org/10.18632/oncotarget.8651

MLA:

Sehm, Tina, et al. "Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema." Oncotarget 7.24 (2016): 36021-36033.

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