Back to Search
Start Over
Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema.
Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema.
- Source :
-
Oncotarget [Oncotarget] 2016 Jun 14; Vol. 7 (24), pp. 36021-36033. - Publication Year :
- 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.<br />Competing Interests: CONFLICTS OF INTERESTS The authors declare no competing financial conflict of interests.
- Subjects :
- Amino Acid Transport System X-AG antagonists & inhibitors
Amino Acid Transport System X-AG metabolism
Animals
Animals, Newborn
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Brain Edema diagnostic imaging
Brain Edema etiology
Brain Neoplasms complications
Brain Neoplasms metabolism
Cell Death drug effects
Cell Line, Tumor
Cell Survival drug effects
Cells, Cultured
Dacarbazine analogs & derivatives
Dacarbazine pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Glioma complications
Glioma metabolism
Humans
Magnetic Resonance Imaging
Rats, Wistar
Temozolomide
Brain Edema prevention & control
Brain Neoplasms drug therapy
Glioma drug therapy
Sulfasalazine pharmacology
Tumor Microenvironment drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27074570
- Full Text :
- https://doi.org/10.18632/oncotarget.8651