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Targeted nitric oxide delivery preferentially induces glioma cell chemosensitivity via altered p53 and O6-Methylguanine-DNA Methyltransferase activity

Authors

  • Shahana Safdar,

    1. School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Dr. NW, Atlanta, Georgia 30332-0100; telephone: 404-894-8795; fax: 404-894-2866
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  • Courtney A. Payne,

    1. Spelman College, 350 Spelman Lane SW, Atlanta, Georgia 30314-4399
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  • Nam H. Tu,

    1. School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Dr. NW, Atlanta, Georgia 30332-0100; telephone: 404-894-8795; fax: 404-894-2866
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  • Lakeshia J. Taite

    Corresponding author
    1. School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Dr. NW, Atlanta, Georgia 30332-0100; telephone: 404-894-8795; fax: 404-894-2866
    • School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Dr. NW, Atlanta, Georgia 30332-0100; telephone: 404-894-8795; fax: 404-894-2866
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  • The authors have no conflict of interest to declare.

Abstract

Glioblastoma multiforme is the most common malignant central nervous system tumor, and also among the most difficult to treat due to a lack of response to chemotherapeutics. New methods of countering the mechanisms that confer chemoresistance to malignant gliomas could lead to significant advances in the quest to identify novel drug combinations or targeted drug delivery systems for cancer therapy. In this study, we investigate the use of a targeted nitric oxide (NO) donor as a pretreatment to sensitize glioma cells to chemotherapy. The protein chlorotoxin (CTX) has been shown to preferentially target glioma cells, and we have developed CTX–NO, a glioma-specific, NO-donating CTX derivative. Pretreatment of cells with CTX–NO followed by 48-h exposure to either carmustine (BCNU) or temozolomide (TMZ), both common chemotherapeutics used in glioma treatment, resulted in increased efficacy of both therapeutics. After CTX–NO exposure, both T98G and U-87MG human malignant glioma cells show increased sensitivity to BCNU and TMZ. Further investigation revealed that the consequences of this combination therapy was a reduction in active levels of the cytoprotective enzyme MGMT and altered p53 activity, both of which are essential in DNA repair and tumor cell resistance to chemotherapy. The combination of CTX–NO and chemotherapeutics also led to decreased cell invasion. These studies indicate that this targeted NO donor could be an invaluable tool in the development of novel approaches to treat cancer. Biotechnol. Bioeng. 2013; 110: 1211–1220. © 2012 Wiley Periodicals, Inc.

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