Convection-enhanced delivery of sulfasalazine prolongs survival in a glioma stem cell brain tumor model

J Neurooncol. 2018 Jan;136(1):23-31. doi: 10.1007/s11060-017-2621-7. Epub 2017 Sep 19.


Expression of CD44 in glioma cells was previously correlated with tumor grade and is considered a stem cell marker. CD44 stabilizes the cystine-glutamate transporter (xCT) and inhibits apoptosis in cancer stem cells (CSCs). Recently it was found that Sulfasalazine (SSZ), an anti-inflammatory drug, acts as an inhibitor of xCT and therefore has potential as a targeted therapy for CSCs. In this study, we tested an efficacy of SSZ against glioma stem cell model developed in rats. As poor penetration of blood-brain barrier resulted in insufficient efficacy of systemic SSZ treatment, SSZ was delivered locally with convection-enhanced delivery (CED). In vitro, expression of CD44 in glioma cells and efficacy of SSZ against glioma cells and glioma stem cells were confirmed. SSZ demonstrated anti-proliferative activity in a dose dependent manner against these cells. This activity was partially reversible with the addition of antioxidant, N-acetyl-L-cysteine, to the medium. In vivo, CED successfully delivered SSZ into the rat brain parenchyma. When delivered at 5 mM concentration, which was the highest possible concentration when SSZ was dissolved in water, CED of SSZ resulted in almost no tissue damage. Against highly malignant bRiTs-G3 brain tumor xenografted rat model; the glioma stem cell model, CED of SSZ at 5 mM concentration induced apoptosis and prolonged survival. Consequently, CED of SSZ induced glioma stem cell death without evidence of tissue damage to normal brain parenchyma. This strategy may be a promising targeted treatment against glioma stem cells.

Keywords: Cancer stem cell; Convection-enhanced delivery; Drug delivery; Malignant glioma; Sulfasalazine.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Antineoplastic Agents / administration & dosage*
  • Apoptosis / drug effects
  • Brain Chemistry
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Convection
  • Disease Models, Animal
  • Drug Delivery Systems
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism
  • Male
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Rats
  • Sulfasalazine / administration & dosage*
  • Survival Analysis
  • Xenograft Model Antitumor Assays


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Hyaluronan Receptors
  • Sulfasalazine