Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system [Xc.sup.-], leading to glutathione depletion

• Published in: Oncogene p. 5951
• Main Authors: Sleire, L, Skeie, B.S, Netland, I.A, Forde, H.E, Dodoo, E, Selheim, F, Leiss, L, Heggdal, J.I, Pedersen, P.-H, Wang, J, Enger, P.O
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 03.12.2015
• Subjects: Cancer; Care and treatment; Dosage and administration; Glioblastoma multiforme; Methods; Oncology, Experimental; Radiotherapy; Sulfasalazine
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.60

Glioblastomas (GBMs) are aggressive brain tumors that always recur after radiotherapy. Cystine, mainly provided by the system [X.sup.-.sub.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.sup.-.sub.c]-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Here, we show that the catalytic subunit of system [X.sup.-.sub.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 doublestrand 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. Oncogene (2015) 34, 5951-5959; doi: 10.1038/onc.2015.60; published online 23 March 2015