Inhibition of multiple protective signaling pathways and Ad.5/3 delivery enhances mda-7/IL-24 therapy of malignant glioma

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1130-1142
Number of pages13
JournalMolecular Therapy
Volume18
Issue number6
DOIs
StatePublished - Jun 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Hamed, H. A., Yacoub, A., Park, M. A., Eulitt, P. J., Dash, R., Sarkar, D., Dmitriev, I. P., Lesniak, M. S., Shah, K., Grant, S., Curiel, D. T., Fisher, P. B., & Dent, P. (2010). Inhibition of multiple protective signaling pathways and Ad.5/3 delivery enhances mda-7/IL-24 therapy of malignant glioma. Molecular Therapy, 18(6), 1130-1142. https://doi.org/10.1038/mt.2010.29