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, Nicolai Savaskan*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

81 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)36021-36033
Number of pages13
JournalOncotarget
Volume7
Issue number24
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Brain swelling
  • Cancer
  • Glioblastoma
  • Tumor microenvironment

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