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lüll Inhibition of multiple protective signaling pathways and Ad 5/3 delivery enhances mda-7/IL-24 therapy of malignant glioma Hamed HA; Yacoub A; Park MA; Eulitt PJ; Dash R; Sarkar D; Dmitriev IP; Lesniak MS; Shah K; Grant S; Curiel DT; Fisher PB; Dent PMol Ther 2010[Jun]; 18 (6): 1130-42We 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.|*Genetic Vectors[MESH]|*Signal Transduction[MESH]|Adenoviridae/*genetics[MESH]|Brain Neoplasms/metabolism/*therapy[MESH]|Glioblastoma/metabolism/*therapy[MESH]|Humans[MESH]|Interleukins/administration & dosage/genetics/*therapeutic use[MESH]|Treatment Outcome[MESH] |