Adenovirus-mediated transfer of BAX driven by the vascular endothelial growth factor promoter induces apoptosis in lung cancer cells.
Apoptosis induction is a promising approach for cancer gene therapy. Bax is a death-promoting member of the Bcl2 family of genes that are intimately involved in apoptosis. Overexpression of BAX protein can accelerate cell death by homodimers that promote apoptosis in a variety of cancer cell lines. The cytotoxic effect of BAX was evaluated in vitro by a recombinant adenovirus system expressing the human BAX gene under control of human vascular endothelial growth factor (VEGF) promoter element (AdVEGFBAX). Overexpression of BAX in human lung carcinoma cells resulted in apoptosis induction, caspase activation, and cell growth suppression, none of which were observed in BEAS-2B normal human bronchial epithelial cells that do not overexpress VEGF under normoxic conditions. To examine the hypoxia responsiveness of the VEGF promoter, lung cancer cells were transiently exposed to hypoxia; this treatment increased enhanced green fluorescent protein (EGFP) expression after AdVEGFEGFP infection in both normal and cancer cell lines, and enhanced apoptosis and decreased the number of surviving cancer cells compared with the Ad/BAX plus Ad/Cre binary adenoviral system. These results suggest a possible therapeutic application of cancer-specific expression of the pro-apoptotic Bax gene driven by the VEGF promoter.
Kaliberov
Sergey A
SA
Departments of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
Buchsbaum
Donald J
DJ
Gillespie
G Yancey
GY
Curiel
David T
DT
Arafat
Waleed O
WO
Carpenter
Mark
M
Stackhouse
Murray A
MA
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis; D015687:Cell Hypoxia; D016228:Endothelial Growth Factors / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D008222:Lymphokines / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016228:Endothelial Growth Factors; D008164:Luminescent Proteins; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins