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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2010-6-1
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pubmed:abstractText |
We have explored the mechanism by which inhibition of multiple cytoprotective cell-signaling pathways enhance melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) toxicity toward invasive primary human glioblastoma multiforme (GBM) cells, and whether improving adenoviral infectivity/delivery of mda-7/IL-24 enhances therapeutic outcome in animals containing orthotopic xenografted GBM cells. The toxicity of a serotype 5 recombinant adenovirus to express MDA-7/IL-24 (Ad.5-mda-7) was enhanced by combined molecular or small molecule inhibition of mitogen-activated extracellular regulated kinase (MEK)1/2 and phosphatidyl inositol 3-kinase (PI3K) or AKT; inhibition of mammalian target of rapamycin (mTOR) and MEK1/2; and the HSP90 inhibitor 17AAG. Molecular inhibition of mTOR/PI3K/MEK1 signaling in vivo also enhanced Ad.5-mda-7 toxicity. In GBM cells of diverse genetic backgrounds, inhibition of cytoprotective cell-signaling pathways enhanced MDA-7/IL-24-induced autophagy, mitochondrial dysfunction and tumor cell death. Due partly to insufficient adenovirus serotype 5 gene delivery this therapeutic approach has shown limited success in GBM. To address this problem, we employed a recombinant adenovirus that comprises the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus expressing MDA-7/IL-24, Ad.5/3-mda-7. Ad.5/3-mda-7 more effectively infected and killed GBM cells in vitro and in vivo than Ad.5-mda-7. Future combinations of these approaches hold promise for developing an effective therapy for GBM.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1525-0024
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pubmed:author |
pubmed-author:CurielDavid TDT,
pubmed-author:DashRupeshR,
pubmed-author:DentPaulP,
pubmed-author:DmitrievIgor PIP,
pubmed-author:EulittPatrick JPJ,
pubmed-author:FisherPaul BPB,
pubmed-author:GrantStevenS,
pubmed-author:HamedHossein AHA,
pubmed-author:LesniakMaciej SMS,
pubmed-author:ParkMargaret AMA,
pubmed-author:SarkarDevanandD,
pubmed-author:ShahKhalidK,
pubmed-author:YacoubAdlyA
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pubmed:issnType |
Electronic
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pubmed:volume |
18
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1130-42
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pubmed:dateRevised |
2011-8-1
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pubmed:meshHeading |
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