Iκbα gene transfer is cytotoxic to squamous-cell lung cancer cells and sensitizes them to tumor necrosis factor-α-mediated cell death

Current paradigms in cancer therapy suggest that activation of nuclear factor-κB (NF-κB) by a variety of stimuli, including some cytoreductive agents, may inhibit apoptosis. Thus, inhibiting NF-κB 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-κB inhibitor IκBα (AdIκBαSR) or β-galactosidase (AdLacZ) were tested alone and in combination with tumor necrosis factor-α (TNF-α) in lung cancer cells for sensitization of the cells to death. Following transduction with AdIκBαSR, lung cancer cells expressed IκBαSR in a dose-dependent manner. Probing nuclear extracts of lung cancer cells with NF-κB-sequence-specific oligonucleotides indicated that there was a minimal amount of NF-κB in the nucleus at baseline and an expected and dramatic increase in nuclear NF-κB following exposure of cells to TNF-α. Control E-1-deleted AdLacZ did not promote NF-κB activation. Importantly, AdIκBαSR-mediated gene transfer resulted in the complete block of nuclear translocation of NF-κB by specific binding of its p65/relA component with transgenic IκBαSR. At the cellular level, transduction with AdIκBαSR 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-α-mediated cytotoxicity, IκBαSR-transduced cells could be sensitized to TNF-α. Consequently, AdIκBαSR transduction followed by exposure to TNF-α uniformly resulted in the death of non-small-cell lung cancer cells. These data suggest that novel approaches incorporating IκBα gene therapy may have a role in the treatment of lung cancer.