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J Thorac Cardiovasc Surg 2002;123:310-317
© 2002 The American Association for Thoracic Surgery

General Thoracic Surgery (GTS)

Inhibition of nuclear factor {kappa}B chemosensitizes non–small cell lung cancer through cytochrome c release and caspase activation

David R. Jones, MDa, R. Michael Broad, PhDa, Laurey D. Comeau, MSb, Sarah J. Parsons, PhDc, Marty W. Mayo, PhDa,b

From the Departments of Surgery,a Biochemistry and Molecular Genetics,b and Microbiology,c The University of Virginia, Charlottesville, Va.

This study was supported by grants to D.R.J. (NCI CA83920-01 and American Cancer Society IRG 81-001-17) and to M.W.M. (NCI CA78595).

Received for publication May 9, 2001. Revisions requested June 6, 2001; revisions received July 10, 2001. Accepted for publication July 11, 2001. Address for reprints: David R. Jones, MD, Department of Surgery, Box 800679, University of Virginia, Charlottesville, VA 22908-0679 (E-mail: djones{at}virginia.edu).

Objective: Although we have previously shown that inhibition of nuclear factor {kappa}B sensitizes non–small cell lung cancer cells to chemotherapy-mediated cell death, the apoptotic pathways mediating this process are unknown. The purpose of this study was to determine whether chemosensitivity after the inhibition of nuclear factor {kappa}B in non–small cell lung cancer cells is a mitochondrial and caspase-mediated process and whether it is dependent on nuclear factor {kappa}B transcriptional activity.
Methods: Previously described H157 non–small cell lung cancer cells were treated with gemcitabine, and DNA fragmentation was determined. Caspase 3, 6, 7, 8, and 9 activity in cytoplasmic extracts was determined fluorometrically. The mitochondrial permeability index and cytosolic cytochrome c levels were also determined. The caspase inhibitor Boc-D, as well as nuclear factor {kappa}B–regulated gene products A1, c-IAP-2, and Bcl-XL, were added to H157 cells lacking nuclear factor {kappa}B and the degree of apoptosis assessed. All experiments were performed in triplicate, and data significance was determined by means of analysis of variance.
Results: Non–small cell lung cancer cells lacking functional nuclear factor {kappa}B (H157I) underwent more apoptosis after chemotherapy than vector control cells (H157V). There was an increase in the mitochondrial permeability index and cytochrome c release after chemotherapy in the H157I cells. H157I cells also had more activation of caspases 3 and 9 than control cells. Inhibition of caspase activity or transfection with nuclear factor {kappa}B–regulated gene products rescued cell death after the inhibition of nuclear factor {kappa}B.
Conclusion: Chemosensitization by means of inhibition of nuclear factor {kappa}B in non–small cell lung cancer cells occurs through increased cytochrome c release and caspase 3 and 9 activation. Inhibition of nuclear factor {kappa}B or its gene products in addition to chemotherapy warrants further study as a treatment strategy in patients with advanced-stage non–small cell lung cancer.




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