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Ann Thorac Surg 2000;70:930-936
© 2000 The Society of Thoracic Surgeons

Original articles: general thoracic

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

David R. Jones, MDa,b, R. Michael Broad, PhDa, Lee V. Madrid, BSb, Albert S. Baldwin, Jr, PhDb, Marty W. Mayo, PhDb

a Department of Surgery, The University of Virginia, Charlottesville, Virginia, USA
b Department of Biology, The University of North Carolina, Chapel Hill, North Carolina, USA

Address reprint requests to Dr Jones, Thoracic and Cardiovascular Surgery, University of Virginia, PO Box 800679, Charlottesville, VA 22908-0679
e-mail: djones{at}virginia.edu

Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Ft Lauderdale, FL, Jan 31–Feb 2, 2000.

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.


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Ann. Thorac. Surg. 2000 70: 936. [Extract] [Full Text] [PDF]



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