title: Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion.
abstract: Glioblastomas (GBMs) are aggressive brain tumors that always recur after radiotherapy. Cystine, mainly provided by the system X(c)(-) antiporter, is a requirement for glioma cell synthesis of glutathione (GSH) which has a critical role in scavenging free radicals, for example, after radiotherapy. Thus, we hypothesized that the X(c)(-)-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Here, we show that the catalytic subunit of system X(c)(-), xCT, was uniformly expressed in a panel of 30 human GBM biopsies. SAS treatment significantly reduced cystine uptake and GSH levels, whereas it significantly increased the levels of reactive oxygen species (ROS) in glioma cells in vitro. Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared with controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients.
authors: Department of Biomedicine, Oncomatrix Research Lab, University of Bergen, Bergen, Norway.
authors: L
authors: L
authors: Sleire
authors: Department of Clinical Medicine, K1, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors: B S
authors: BS
authors: Skeie
authors: Department of Biomedicine, Oncomatrix Research Lab, University of Bergen, Bergen, Norway.
authors: I A
authors: IA
authors: Netland
authors: Department of Biomedicine, Oncomatrix Research Lab, University of Bergen, Bergen, Norway.
authors: H E
authors: HE
authors: Førde
authors: Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
authors: E
authors: E
authors: Dodoo
authors: Department of Biomedicine, Proteomics Unit (PROBE), University of Bergen, Bergen, Norway.
authors: F
authors: F
authors: Selheim
authors: Department of Biomedicine, Oncomatrix Research Lab, University of Bergen, Bergen, Norway.|Neuro Clinic, Haukeland University Hospital, Bergen, Norway.
authors: L
authors: L
authors: Leiss
authors: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors: J I
authors: JI
authors: Heggdal
authors: Department of Clinical Medicine, K1, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors: P-H
authors: PH
authors: Pedersen
authors: Department of Biomedicine, Oncomatrix Research Lab, University of Bergen, Bergen, Norway.
authors: J
authors: J
authors: Wang
authors: Department of Biomedicine, Oncomatrix Research Lab, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors: P Ø
authors: PØ
authors: Enger
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D003553:Cystine / Q000378:metabolism*; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D058492:Drug Repositioning; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016634:Radiosurgery; D051381:Rats; D012460:Sulfasalazine / Q000008:administration & dosage* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D011838:Radiation-Sensitizing Agents; C118895:SLC7A11 protein, human; D012460:Sulfasalazine; D003553:Cystine; D004247:DNA; D005978:Glutathione