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Potentiation of Chemotherapeutic Agents following Antagonism of Nuclear Factor kappa B in Human Gliomas

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Abstract

Future success using chemotherapy against human gliomas may result from exploiting unique molecular vulnerabilities of these tumors. Chemotherapy frequently results in DNA damage. When such damage is sensed by the cell, programmed cell death, or apoptosis, may be initiated. However, chemotherapy-induced DNA damage may activate nuclear factor kappa B (NF-κB) and block apoptosis. We inhibited NF-κB using a gene therapy approach to determine whether this would render human glioma cells more susceptible to chemotherapy. U87 and U251 glioma cell lines were infected with either treatment adenovirus containing the gene for a mutant non-degradable form of IκBα, which is an inhibitor of NF-κB nuclear translocation, or empty control virus. Following viral infection, cells were treated either with BCNU, carboplatin, tumor necrosis factor alpha (TNF-α), or SN-38.

Chemotherapy resulted in a marked increase in active intranuclear NF-κB. This response was greatly decreased by insertion of the mutant repressor gene. Similarly, a significant increase in cell killing by all chemotherapy age was demonstrated following infection with treatment virus. Expression of the mutant repressor gene also resulted in increased apoptosis by TUNEL assay following chemotherapy.

Numerous genes are responsible for glioma chemoresistance. DNA damage by chemotherapy may induce the antiapoptotic factor NF-κB and prevent programmed cell death. Insertion of a mutant inhibitor of NF-κB strips cells of this antiapoptotic defense and renders them more susceptible to killing by chemotherapy via increased apoptosis.

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Authors and Affiliations

  1. Division of Neurosurgery, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Kyle D. Weaver & Matthew G. Ewend

  2. Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Susan Yeyeodu

  3. Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA

    James C. Cusack Jr.

  4. Department of Cell Biology, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Albert S. Baldwin Jr.

  5. Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Albert S. Baldwin Jr. & Matthew G. Ewend

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  1. Kyle D. Weaver
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  2. Susan Yeyeodu
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  3. James C. Cusack Jr.
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  4. Albert S. Baldwin Jr.
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  5. Matthew G. Ewend
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Weaver, K.D., Yeyeodu, S., Cusack, J.C. et al. Potentiation of Chemotherapeutic Agents following Antagonism of Nuclear Factor kappa B in Human Gliomas. J Neurooncol 61, 187–196 (2003). https://doi.org/10.1023/A:1022554824129

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