SC-05DOPAMINE RECEPTOR ANTAGONISTS ARE SELECTIVE INHIBITORS OF GLIOBLASTOMA STEM CELLS THROUGH IMPAIRMENT OF AUTOPHAGY

Glioblastoma is an incurable cancer. The tumorigenic potential of glioblastoma resides within cells with a stem cell phenotype called glioblastoma stem cells. In order to identify novel glioblastoma drugs, we interrogated a library of 680 neuromodulatory compounds for their activity on glioblastoma derived neural stem cells (GNS), normal human fetal neural stem (NS) cells and normal fibroblasts to identify selective inhibitors. Compounds modulating dopaminergics, serotonergics and cholinergics pathways are enriched in the hits. In particular, two dopamine receptor antagonists demonstrated great selectivity for GNS cells and were synergistic with the chemotherapeutic drug temozolomide. These compounds reduced the clonogenic potential of primary glioblastoma cells and the growth of glioblastoma xenografts. Primary glioblastoma tumor and GNS cells expressed dopamine receptor. Mechanistic studies by pharmalogical inhibition and genetic knockdown of dopamine receptor suppressed glioblastoma stem cells growth and the ERK1/2 pathway. Furthermore, genome wide expression array showed downregulation of genes involved in cell cycle progression and upregulation of genes involved in autophagy. Further investigation revealed accumulations of autophagic vacuole with increased p62 suggesting a block in autophagy leading to cell death. This study identified new candidates for glioblastoma therapy and suggests neurochemical modifications should be focus for further drug development.