Title

Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2010-09-01

Document Type

Article

Subjects

Glioma; Dacarbazine; Receptors, Notch; Amyloid Precursor Protein Secretases

Disciplines

Biochemistry, Biophysics, and Structural Biology | Cancer Biology | Pharmacology, Toxicology and Environmental Health

Abstract

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.

DOI of Published Version

10.1158/0008-5472.CAN-10-1378

Source

Cancer Res. 2010 Sep 1;70(17):6870-9. Epub 2010 Aug 24. doi: 10.1158/0008-5472.CAN-10-1378

Journal/Book/Conference Title

Cancer Research

Related Resources

Link to article in PubMed

PubMed ID

20736377

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