Abstract 1789: Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife surgery by blocking cystine uptake through System XC−, leading to gluthatione depletion

Abstract

Abstract Glioblastomas (GBMs) are lethal cancers and inherently resistant to radiotherapy. Established treatments including surgery, radio- and chemotherapy have a limited efficacy, and the median survival is approximately 14.6 months. Thus, treatment resistance represents a major challenge in the clinical management of these patients, and new therapies are urgently needed. We hypothesized that the Xc−-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Expression of the catalytic subunit of system Xc−, xCT, was found in a panel of 30 human GBM biopsies. Sections from normal brain tissue displayed only weak immunopositivity, thus our findings therefore suggest that xCT expression is common to most GBMs, which together with its low expression in normal brain tissue could provide a therapeutic window. SAS treatment dramatically reduced cysteine-uptake and glutathione (GSH) levels in glioma cells in vitro and markedly increased the levels of reactive oxygen species (ROS). 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 to 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. We are currently preparing a clinical trial for patients with GBM recurrences combining pre-treatment with SAS and GKRS. Citation Format: Linda Sleire, Bente Sandvei Skeie, Inger Anne Netland, Hilde Elise Førde, Ernest Dodoo, Frode Selheim, Lina Leiss, Jian Wang, Jan Heggdal, Paal-Henning Pedersen, Per Øyvind Enger. Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife surgery by blocking cystine uptake through System XC−, leading to gluthatione depletion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1789. doi:10.1158/1538-7445.AM2015-1789