Am. J. Respir. Cell Mol. Biol., Volume 21, Number 2, August, 1999 238-245

IB Gene Transfer Is Cytotoxic to Squamous-Cell Lung Cancer Cells and Sensitizes Them to Tumor Necrosis Factor--Mediated Cell Death

Raj K. Batra, Denis C. Guttridge, David A. Brenner, Steven M. Dubinett, Albert S. Baldwin, and Richard C. Boucher

Department of Medicine and The Wadsworth Pulmonary Immunology Laboratory, West Los Angeles-Veterans Administration Medical Center/University of California Los Angeles, Los Angeles, California; and Cystic Fibrosis/ Pulmonary Research and Treatment Center, Department of Medicine, and the Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Current paradigms in cancer therapy suggest that activation of nuclear factor-B (NF-B) by a variety of stimuli, including some cytoreductive agents, may inhibit apoptosis. Thus, inhibiting NF-B activation may sensitize cells to anticancer therapy, thereby providing a more effective treatment for certain cancers. E-1-deleted adenoviral (Ad) vectors encoding a "superrepressor" form of the NF-B inhibitor IB (AdIBSR) or -galactosidase (AdLacZ) were tested alone and in combination with tumor necrosis factor- (TNF-) in lung cancer cells for sensitization of the cells to death. Following transduction with AdIBSR, lung cancer cells expressed IBSR in a dose-dependent manner. Probing nuclear extracts of lung cancer cells with NF-B-sequence-specific oligonucleotides indicated that there was a minimal amount of NF-B in the nucleus at baseline and an expected and dramatic increase in nuclear NF-B following exposure of cells to TNF-. Control E-1-deleted AdLacZ did not promote NF-B activation. Importantly, AdIBSR-mediated gene transfer resulted in the complete block of nuclear translocation of NF-B by specific binding of its p65/relA component with transgenic IBSR. At the cellular level, transduction with AdIBSR resulted in increased cytotoxicity in lung cancer cells as opposed to transduction with equivalent doses of AdLacZ. In addition, whereas the parental cells were resistant to TNF--mediated cytotoxicity, IBSR-transduced cells could be sensitized to TNF-. Consequently, AdIBSR transduction followed by exposure to TNF- uniformly resulted in the death of non-small-cell lung cancer cells. These data suggest that novel approaches incorporating IB gene therapy may have a role in the treatment of lung cancer.

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