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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 B chemosensitizes non–small cell lung cancer through cytochrome c release and caspase activation

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 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 B in non–small cell lung cancer cells is a mitochondrial and caspase-mediated process and whether it is dependent on nuclear factor 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 B–regulated gene products A1, c-IAP-2, and Bcl-X_L, were added to H157 cells lacking nuclear factor 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 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 B–regulated gene products rescued cell death after the inhibition of nuclear factor B.
Conclusion: Chemosensitization by means of inhibition of nuclear factor B in non–small cell lung cancer cells occurs through increased cytochrome c release and caspase 3 and 9 activation. Inhibition of nuclear factor 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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