γ-Secretase Inhibitor-I Enhances Radiosensitivity of Glioblastoma Cell Lines by Depleting CD133+ Tumor Cells

Background and Aims. Glioblastoma is a deadly primary brain tumor with great resistance to radiotherapy. To reverse its radioresistance is important for improving prognosis. Gamma-secretase inhibitors (GSI) have been proven to have anti-tumor effects, yet the knowledge of their influences on glioblastomas is still limited. Methods. The cytotoxic effects of GSI-I (a tripeptide GSI) on glioblastoma cell lines U87 and U251 were assessed by MTT assay, and the low concentration that did not induce significant cell death was determined. The in vitro radiosensitization effects of this low concentration of GSI-I were evaluated by cell colony forming assays. The CD133(+) cell fractions before and after radiation with or without treatment of GSI-I were analyzed by flow cytometry. Then CD133(+) and CD133(-) glioblastorna cells were sorted by magnetic activated cell sorting (MACS), and the radiosensitization effects of GSI-I on the two cell subtypes were investigated separately. Finally, the cytotoxic effects of GSI-I on CD133(+) and CD133(-) glioblastoma cells were examined, respectively, and the expression of the Notch pathway components between the two cell subtypes were compared. In addition, the anti-tumor effects of GSI-I were confirmed by in vivo experiments. Results. GSI-I at a low concentration sensitized U87 and U251 cells to radiation by depletion of radioresistant CD133(+) cells. CD133(+) U87/U251 cells displayed preferential sensitivty to low concentrations of GSI-I, which may be related to the higher expression of the Notch signaling pathway in these cells. Conclusions. Combining GSI-I with radiotherapy may represent a promising strategy for treating radioresistant gliomas. (C) 2010 IMSS. Published by Elsevier Inc.