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

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Abstract

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.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (Grant No. #26293319 to R.S.). The authors would like to thank Enago (http://www.enago.jp) for the English language review.

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Authors and Affiliations

  1. Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Shinya Haryu, Ryuta Saito, Wenting Jia, Takuhiro Shoji, Yui Mano, Aya Sato, Masayuki Kanamori, Yukihiko Sonoda & Teiji Tominaga

  2. Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan

    Oltea Sampetrean & Hideyuki Saya

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  1. Shinya Haryu
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  2. Ryuta Saito
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Correspondence to Ryuta Saito.

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No author has a personal or institutional financial interest in the drugs, materials, or devices described in this paper.

Ethical approval

All animal protocols in this study were approved by the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine.

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Haryu, S., Saito, R., Jia, W. et al. Convection-enhanced delivery of sulfasalazine prolongs survival in a glioma stem cell brain tumor model. J Neurooncol 136, 23–31 (2018). https://doi.org/10.1007/s11060-017-2621-7

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  • DOI: https://doi.org/10.1007/s11060-017-2621-7

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