Radiation is one of the main treatment modalities in lung cancer, but low sensitivity and acquired resistance of lung cancer cells to radiation frequently result in treatment failure. The activation of nuclear factor (NF)-κB is reportedly the main mechanism by which cancer cells exhibit resistance to external stresses, such as chemotherapy or radiation therapy. In this study, we blocked the activation of NF-κB by adenovirus-expressing IκBα-SR and investigated the effect this had on radiation sensitivity. Transduction with ad-IκBα effectively blocked the activation of NF-κB by radiation in all the cancer cell lines tested, except for NCI H460. Clonogenic assay after radiation demonstrated that ad-IκBα transduction enhanced the sensitivity to radiation of the lung cancer cell lines and HeLa cells, except for NCI H460. The radiosensitizing effect of IκBα was more potent in lung cancer cell lines with radioresistance (SKMESres) (sensitizer enhancement ratio 1:61). From these findings, NF-κB blockade by ad-IκBα enhanced the radiation sensitivity and also abolished the acquired radiation resistance of lung cancer cell lines. This study provides a therapeutic rationale for combining an NF-κB-blocking strategy with radiation to both increase sensitivity and overcome acquired resistance to radiation.

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