Abstract 1590: Sulfasalazine sensitizes glioblastoma cells to radiation treatment.

Abstract Glioblastoma (GBM) is a lethal cancer with a limited response to ionizing radiation. Recent studies suggest that Sulfasalazine (SAS), a drug used to treat inflammatory bowel disease, inhibits the Xc− antiporter system in glioma cells, thereby blocking their uptake of cystein. Since the availability of cystein is a rate limiting step in intracellular antioxidant production, we wanted to investigate whether sulfasalazine sensitizes glioma cells to radiation. Expression of xCT, the catalytic subunit of system Xc−, was found in 30 patient GBM biopsies. SAS effect on glioma cell growth was investigated using an electric cell substrate impedance sensing (ECIS) instrument. All glioma cell lines showed altered growth curves in response to SAS treatment. To assess the effect of blocking the antiporter, intracellular levels of the antioxidant glutathione were measured. With increasing doses of SAS, glutathione levels decreased in a dose response manner. In addition, cysteine was added to the medium to see if the toxic effects of SAS could be counteracted. Furthermore, accumulation of reactive oxygen species upon SAS treatment was measured. Glioma cells were also treated with escalating doses of SAS, alone or in combination with radiation (8 Gy). The presence of double stranded breaks increased markedly in the irradiated samples and also somewhat with increasing doses with SAS. In addition, cell death, viability and clonogenicity were investigated using live/dead staining, the MTS assay and the clonogenic assay. All treatment groups exhibited increased rates of cell death compared to untreated controls. A combination of SAS and radiation resulted in higher levels of cell death, than radiation or SAS administered alone. Furthermore we continued with implantation of human GBMs into the brain of Nude rats. These animals were treated with Gamma Knife Radiosurgery alone or in combination with SAS. SAS were administered as a pre-treatment for three days before Radiosurgery. The rats receiving the combination treatment lived significantly longer compared to either treatment alone. Interestingly, the animals only receiving pre-treatment with SAS for three days lived significantly longer compared to the untreated controls, although this was not statistically significant. We are currently preparing a clinical trial for patients with GBM recurrences combining pre-treatment with Sulfasalazine and Gamma Knife Radiosurgery. Citation Format: Linda Sleire, Bente S. Skeie, Inger A. Netland, Jan Heggdal, Paal-Henning Pedersen, Per Ø. Enger. Sulfasalazine sensitizes glioblastoma cells to radiation treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1590. doi:10.1158/1538-7445.AM2013-1590