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March 29, 2011; 76 (13) Articles

Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy

Xing Gong, Philip H. Schwartz, Mark E. Linskey, Daniela A. Bota
First published February 23, 2011, DOI: https://doi.org/10.1212/WNL.0b013e318212a89f
Xing Gong
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Mark E. Linskey
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Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy
Xing Gong, Philip H. Schwartz, Mark E. Linskey, Daniela A. Bota
Neurology Mar 2011, 76 (13) 1126-1134; DOI: 10.1212/WNL.0b013e318212a89f

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Abstract

Objectives: New data suggest that glioma stem-like cells (GSCs) and neural stem/progenitor cells (NSCs) may share common origins. GSCs drive tumor proliferation and appear to be resistant to classic chemotherapy, while the effects of chemotherapy on NSCs are not well studied. As the role of NSCs in learning and memory is increasingly recognized, we need to identify drugs that reduce neurotoxicity but are still effective against glial tumors.

Methods: We treated 3 human NSC cultures and multiple low- and high-grade GSC cultures with the commonly used agents temozolomide (TMZ) and cisplatin (CIS), and with 2 newer, promising drugs: the proteasome inhibitor bortezomib (BTZ) and the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL). We measured cell survival, proliferation, cell death induction, and drug resistance markers.

Results: TMZ decreased NSC viability, while minimally affecting GSCs. TMZ induced NSC death, which was partially compensated for by increased proliferation. CIS had similar effects. The NSC's sensitivity to TMZ and CIS correlated with low expression of the multidrug resistance gene ABCG2, but not of MGMT or MSH1/MLH2. BTZ caused an 80%decrease in GSCs, while minimally affecting NSCs. GSCs had lower proteasome levels and activity after BTZ treatment. ERL treatment also decreased GSC numbers, but not NSC viability, which correlated with low EGFR expression in NSCs compared to GSCs.

Conclusions: Newer chemotherapy agents ERL and BTZ are effective against GSCs yet produce minimal effects on NSCs, while the older drugs TMZ and CIS are more toxic for NSCs than for GSCs. The identification and testing of more selective drugs is clearly warranted.

Footnotes

  • Study funding: Supported in part by start-up funds to D. Bota from the University of California, Irvine, and by Children's Hospital of Orange County through the National Human Neural Stem Cell Resource.

  • BTZ
    bortezomib
    CIS
    cisplatin
    ERL
    erlotinib
    GSC
    glioma stem-like cell
    MGMT
    methyl-guanine methyl transferase
    NSC
    neural stem/progenitor cell
    TMZ
    temozolomide

  • Editorial, page 1118

  • Supplemental data at www.neurology.org

  • Received May 20, 2010.
  • Accepted October 15, 2010.
  • Copyright © 2011 by AAN Enterprises, Inc.
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Disputes & Debates: Rapid online correspondence

  • Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy
    • Marc C Chamberlain, Provider, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliancechambemc@u.washington.edu
    Submitted August 08, 2011
  • Reply from the Authors
    • Daniela A. Bota, Assistant Professor of Neurology, UC Irvine Medical Center, Irvine, CAdbota@uci.edu
    • Mark E. Linskey, Philip H. Schwartz
    Submitted August 08, 2011
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