Retracted: Inhibition of multiple protective signaling pathways and Ad.5/3 delivery enhances mda-7/IL-24 therapy of malignant glioma.
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.
Hamed
Hossein A
HA
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Yacoub
Adly
A
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Park
Margaret A
MA
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Eulitt
Patrick J
PJ
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Dash
Rupesh
R
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Sarkar
Devanand
D
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.
Dmitriev
Igor P
IP
Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Lesniak
Maciej S
MS
The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
Shah
Khalid
K
Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Grant
Steven
S
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.
Curiel
David T
DT
Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Fisher
Paul B
PB
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.
Dent
Paul
P
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.
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
D007378:Interleukins; D000099180:Interleukin-24