Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2010-09-01Keywords
GliomaDacarbazine
Receptors, Notch
Amyloid Precursor Protein Secretases
Biochemistry, Biophysics, and Structural Biology
Cancer Biology
Pharmacology, Toxicology and Environmental Health
Metadata
Show full item recordAbstract
Malignant gliomas are treated with a combination of surgery, radiation, and temozolomide (TMZ), but these therapies ultimately fail due to tumor recurrence. In glioma cultures, TMZ treatment significantly decreases neurosphere formation; however, a small percentage of cells survive and repopulate the culture. A promising target for glioma therapy is the Notch signaling pathway. Notch activity is upregulated in many gliomas and can be suppressed using gamma-secretase inhibitors (GSI). Using a neurosphere recovery assay and xenograft experiments, we analyzed if the addition of GSIs with TMZ treatment could inhibit repopulation and tumor recurrence. We show that TMZ + GSI treatment decreased neurosphere formation and inhibited neurosphere recovery. This enhancement of TMZ treatment occurred through inhibition of the Notch pathway and depended on the sequence of drug administration. In addition, ex vivo TMZ + GSI treatment of glioma xenografts in immunocompromised mice extended tumor latency and survival, and in vivo TMZ + GSI treatment blocked tumor progression in 50% of mice with preexisting tumors. These data show the importance of the Notch pathway in chemoprotection and repopulation of TMZ-treated gliomas. The addition of GSIs to current treatments is a promising approach to decrease brain tumor recurrence.Source
Cancer Res. 2010 Sep 1;70(17):6870-9. Epub 2010 Aug 24. doi: 10.1158/0008-5472.CAN-10-1378DOI
10.1158/0008-5472.CAN-10-1378Permanent Link to this Item
http://hdl.handle.net/20.500.14038/25996PubMed ID
20736377Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-10-1378