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