Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue.

Abstract

Our previous studies demonstrated that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7 (Ad-mda7) leads to rapid induction of double-stranded RNA-dependent protein kinase (PKR) and activation of its downstream targets, resulting in apoptosis induction in human lung cancer cells. Here, we report that Ad-mda7 and the benzoquinone ansamycin geldanamycin (GA) interact in a highly synergistic manner to induce cell death in human lung cancer cells. Co-administration of Ad-mda7 and GA did not modify expression of MDA-7, and was not associated with further PKR induction and activation; instead the enhanced cytotoxicity of this combination was associated with inactivation of AKT by GA. By surface staining using anti-E-cadherin monoclonal antibody and flow cytometry, we found that treatment with the combination of Ad-mda7 and GA increased E-cadherin levels in these cancer cells. Ad-mda7 and GA cotreatment also inhibited lung cancer cell motility by increasing the beta-catenin/E-cadherin association. Moreover, combination of GA derivative 17-allyl-amino, 17-demethoxygeldanamycin (17AAG), with Ad-mda7 resulted in enhancement of cell death in A549 and H460 human lung cancer cells.

• Authors: A Pataer, D Bocangel, S Chada, J A Roth, K K Hunt, S G Swisher
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 14 Issue 1 Pg. 12-8 (Jan 2007) ISSN: 0929-1903 [Print] England
• PMID: 17024233 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoquinones
• Lactams, Macrocyclic
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• geldanamycin

Topics

• Adenoviridae (genetics)
• Benzoquinones (chemistry, pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Flow Cytometry
• Fluorescent Antibody Technique
• Genetic Vectors
• Humans
• Lactams, Macrocyclic (chemistry, pharmacology)
• Lung Neoplasms (pathology)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)