Inhibition of NF-kappa B sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis

Background. Most non-small cell lung cancers (NSCLC) are chemoresistant. Identification and modulation of chemoresistance cell-signaling pathways may sensitize NSCLC to chemotherapy and improve patient outcome. The purpose of this study was to determine if chemotherapy induces nuclear factor-kappa B (NF-kappa B) activation in NSCLC in vitro and whether inhibition of NF-kappa B would sensitize tumor cells to undergo chemotherapy-induced apoptosis. Methods. Non-small cell lung cancer cells were treated with gemcitabine, harvested, and nuclear extracts analyzed for NF-kappa B DNA binding by electrophoretic mobility shift assays. Additionally, NSCLC cells that stably expressed a plasmid encoding the superrepressor I kappa B alpha protein (H157I) or a vector control (H157V) were generated. These cells were then treated with gemcitabine and apoptosis determined by terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay. Results. Chemotherapy induced NF-kappa B nuclear translocation and DNA binding in all NSCLC cell lines. H157I cells had enhanced cell death compared with H157V cells, suggesting that NF-kappa B is required for cell survival after chemotherapy. The observed cell death following the loss of NF-kappa B occurred by apoptosis. Conclusions. Inhibition of chemotherapy-induced NF-kappa B activation sensitizes NSCLC to chemotherapy-induced apoptosis in vitro. Novel treatment strategies for patients with advanced NSCLC may involve chemotherapy combined with inhibition of NF-kappa B-dependent cell-survival pathways. (Ann Thorac Surg 2000;70:930-7) (C) 2000 by The Society of Thoracic Surgeons.