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Potentiation of chemotherapeutic agents following antagonism of nuclear factor kappa B in human gliomas.

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-kappaB) and block apoptosis. We inhibited NF-kappaB 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 IkappaBalpha, which is an inhibitor of NF-kappaB nuclear translocation, or empty control virus. Following viral infection, cells were treated either with BCNU, carboplatin, tumor necrosis factor alpha (TNF-alpha), or SN-38. Chemotherapy resulted in a marked increase in active intranuclear NF-kappaB. 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-kappaB and prevent programmed cell death. Insertion of a mutant inhibitor of NF-kappaB strips cells of this antiapoptotic defense and renders them more susceptible to killing by chemotherapy via increased apoptosis.

journal_name

J Neurooncol

journal_title

Journal of neuro-oncology

authors

Weaver KD,Yeyeodu S,Cusack JC Jr,Baldwin AS Jr,Ewend MG

doi

10.1023/a:1022554824129

subject

Has Abstract

pub_date

2003-02-01 00:00:00

pages

187-96

issue

3

eissn

0167-594X

issn

1573-7373

journal_volume

61

pub_type

杂志文章

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