Abstract
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioma stem cells (GSCs), a subpopulation of GBM cells with stem cell properties, are responsible for the tumor initiation and recurrence, and therapeutic resistance. To develop novel therapeutic agents for sphere-forming patient derived GSCs, we utilized a new drug screening system and FDA approved drugs. The cell viability of the drugs on GSCs and normal human dermal fibroblast (nHDF) cells was determined by CellTiter-Glo 3D Cell Viability Assay or MTT assay. The relative cytotoxicity of drugs was compared with LC(50). We identified 8 drugs, including 4 that have not been studied for GSCs, which showed strong cytotoxic effect on sphere-forming GSCs but were not toxic to nHDF cells in in vitro cell cultures. The LC(50) of these identified drugs to GSCs is 10 fold to over 100 fold less than that for normal cells. Among the identified drugs, only one drug was not cytotoxic to GBM cells but toxic to GSCs. Based on the LC(50) data and previous reports for the drugs on GSCs, we determined anti-tumor effects of two drugs in orthotopic brain tumor mouse models of human GBM cells. Animals treated with either drug (10 mg/kg once a week for 7 weeks or 30 mg/kg twice a week for 4 weeks) had significantly greater survival in Kaplan-Meier survival curve compared to vehicle treated control mice (p=0.03 or 0.05 in logrank test). Studies for structure-activity-relationship and mechanism of action are on-going. In summary, the present results provide compelling evidence that repurposing of approved drugs can be developed for GSCs and the study identified several selective cytotoxic drugs against sphere-forming GSCs. [This work was supported in part by the Tara Leah Witmer Endowment]