Inhibition of Multiple Protective Signaling Pathways and Ad.5/3 Delivery Enhances mda-7/IL-24 Therapy of Malignant Glioma |
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| Authors: | Hossein A Hamed Adly Yacoub Margaret A Park Patrick J Eulitt Rupesh Dash Devanand Sarkar Igor P Dmitriev Maciej S Lesniak Khalid Shah Steven Grant David T Curiel Paul B Fisher Paul Dent |
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| Affiliation: | 1. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA;2. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA;3. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA;4. Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA;5. The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA;6. Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;7. Department of Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA;8. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA |
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| Abstract: | 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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