title: Retracted: Inhibition of multiple protective signaling pathways and Ad.5/3 delivery enhances mda-7/IL-24 therapy of malignant glioma.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Eulitt
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; Department of Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA. Electronic address: pdent@vcu.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D015398:Signal Transduction; D016896:Treatment Outcome; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D000099180:Interleukin-24