Telomestatin Impairs Glioma Stem Cell Survival and Growth through the Disruption of Telomeric G-Quadruplex and Inhibition of the Proto-oncogene, c-Myb

摘要: Purpose: Glioma stem cells (GSC) are a critical therapeutic target of glioblastoma multiforme (GBM). Experimental Design: The effects G-quadruplex ligand, telomestatin, were evaluated using patient-derived GSCs, non-stem tumor (non-GSC), and normal fetal neural precursors in vitro vivo . molecular targets telomestatin determined by immunofluorescence situ hybridization (iFISH) cDNA microarray. data then validated functional assays, as well immunohistochemistry against 90 clinical samples. Results: Telomestatin impaired the maintenance GSC cell state inducing apoptosis migration potential GSCs was also treatment. In contrast, both non-GSCs relatively resistant to telomestatin. Treatment GSC-derived mouse intracranial tumors reduced sizes without noticeable death brains. iFISH revealed telomeric non-telomeric DNA damage but not non-GSCs. microarray identified proto-oncogene, c-Myb , novel pharmacodynamic analysis telomestatin-treated tumor-bearing brains showed reduction Knockdown phenocopied restoring overexpression partially rescued phenotype. Finally, expression markedly elevated surgical specimens GBMs compared with tissues. Conclusions: These indicate that potently eradicates through telomere disruption inhibition, this study suggests GSC-directed strategy for GBMs. Clin Cancer Res; 18(5); 1268–80. ©2012 AACR