Adenovirus-mediated inhibitor κB gene transfer improves the chemosensitivity to anticancer drugs in human lung cancer in vitro and in vivo

Background: Nuclear factor kappaB (NFκB) is a transcription factor which is importantly implicated in cancer cell growth. In a previous report, we confirmed that lung cancer cell growth was suppressed significantly by the blockade of NFκB function. In this study the combination effect of chemotherapy and inhibition of NFκB on the human lung cancer cell line, NCI-H460, in vitro and in vivo was investigated. Materials and Methods: In the in vitro experiment, 50% of cell growth inhibitory concentrations (IC ₅₀) of chemotherapy agents were determined alone or when combined with adenovirus mediated IκBα gene transfer. Annexin-V/PI stain and caspase 3 activity measurement were used to detect the apoptosis caused by treatment. In the in vivo experiment, the tumor growth suppressive effect of combination treatment was evaluated for tumor-bearing mice. NFκB, p53 and VEGF expression in the tumors were also analyzed immunohistologically. Results: Several chemotherapy agents, including paclitaxel, showed lower IC₅₀s when combined with AdIκBα infection in vitro. Apoptosis through activation of the caspase 3 pathway was enhanced by the combination treatment. For established NCI-H460 tumors, combined treatment significantly inhibited tumor growth. Immunohistochemical staining showed increased expression of p65 after paclitaxel treatment, while paclitaxel in combination with AdIκBα intratumoral injection eliminated this expression accompanied by the slightly reduced expression of VEGF, with stable p53 status. Conclusion: A combination of chemotherapy and IκBα could inhibit tumor growth effectively by blocking the expression of NFκB and inducing apoptosis. Moreover, it might allow reduction of the dose of chemotherapy agents and provide benefit for clinical application.