Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb.

Abstract

PURPOSE:

Glioma stem cells (GSC) are a critical therapeutic target of glioblastoma multiforme (GBM).

EXPERIMENTAL DESIGN:

The effects of a G-quadruplex ligand, telomestatin, were evaluated using patient-derived GSCs, non-stem tumor cells (non-GSC), and normal fetal neural precursors in vitro and in vivo. The molecular targets of telomestatin were determined by immunofluorescence in situ hybridization (iFISH) and cDNA microarray. The data were then validated by in vitro and in vivo functional assays, as well as by immunohistochemistry against 90 clinical samples.

RESULTS:

Telomestatin impaired the maintenance of GSC stem cell state by inducing apoptosis in vitro and in vivo. The migration potential of GSCs was also impaired by telomestatin treatment. In contrast, both normal neural precursors and non-GSCs were relatively resistant to telomestatin. Treatment of GSC-derived mouse intracranial tumors reduced tumor sizes in vivo without a noticeable cell death in normal brains. iFISH revealed both telomeric and non-telomeric DNA damage by telomestatin in GSCs but not in non-GSCs. cDNA microarray identified a proto-oncogene, c-Myb, as a novel molecular target of telomestatin in GSCs, and pharmacodynamic analysis in telomestatin-treated tumor-bearing mouse brains showed a reduction of c-Myb in tumors in vivo. Knockdown of c-Myb phenocopied telomestatin-treated GSCs both in vitro and in vivo, and restoring c-Myb by overexpression partially rescued the phenotype. Finally, c-Myb expression was markedly elevated in surgical specimens of GBMs compared with normal tissues.

CONCLUSIONS:

These data indicate that telomestatin potently eradicates GSCs through telomere disruption and c-Myb inhibition, and this study suggests a novel GSC-directed therapeutic strategy for GBMs.

• Authors: Takeshi Miyazaki, Yang Pan, Kaushal Joshi, Deepti Purohit, Bin Hu, Habibe Demir, Sarmistha Mazumder, Sachiko Okabe, Takao Yamori, Mariano Viapiano, Kazuo Shin-ya, Hiroyuki Seimiya, Ichiro Nakano
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 5 Pg. 1268-80 (Mar 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22230766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• MAS1 protein, human
• Oxazoles
• Proto-Oncogene Mas
• telomestatin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• DNA Damage (drug effects)
• G-Quadruplexes (drug effects)
• Gene Expression
• Genes, myb (drug effects)
• Glioma (drug therapy, genetics)
• Humans
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Neural Stem Cells (drug effects)
• Oxazoles (administration & dosage, pharmacology)
• Proto-Oncogene Mas
• Xenograft Model Antitumor Assays