Telomerase inhibition as a novel therapy for pediatric ependymoma.
Ependymomas are the third most common pediatric brain tumor with an overall survival of approximately 50%. Recently, we showed that telomerase [human telomerase reverse transcriptase (hTERT)] expression is a predictor of poor outcome in pediatric ependymoma. Thus, we hypothesized that ependymomas with functional telomerase may behave more aggressively and that these patients may benefit from anti-telomerase therapy. To address our hypothesis, we investigated the effect of telomerase inhibition on primary ependymoma cells harvested at the time of surgery, as no animal models or established cell lines are readily available for this tumor. The cells were characterized for glial fibrillary acidic protein (GFAP) and hTERT expression, initial telomere length and telomerase activity. They were then subjected to telomerase inhibition (MST-312, 1 microM) and tested for effects on cell viability (MTT assay), proliferation (MIB-1), apoptosis (cleaved caspase 3) and DNA damage (gammaH2AX). After 72 h of telomerase inhibition, primary ependymoma cells showed a significant decrease in cell number (P < 0.001), accompanied by increased DNA damage (gammaH2AX expression) (P < 0.01) and decreased proliferative index (MIB-1) (P < 0.01). Half showed an increase in apoptosis (cleaved caspase 3). These data suggest that telomerase inhibition may be an effective adjuvant therapy in pediatric ependymoma, potentially inducing tumor growth arrest in the short term, independent of telomere shortening.
Wong
Vincent C H
VC
Division of Pathology, The Hospital for Sick Children, Toronto, Canada.
Morrison
Andrew
A
Tabori
Uri
U
Hawkins
Cynthia E
CE
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D004249:DNA Damage / Q000187:drug effects; D004806:Ependymoma / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
D001549:Benzamides; D005904:Glial Fibrillary Acidic Protein; C470197:MST 312; D019098:Telomerase