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J Thorac Cardiovasc Surg 2004;128:740-748
© 2004 The American Association for Thoracic Surgery

General thoracic surgery

Proteasome inhibition sensitizes non–small cell lung cancer to histone deacetylase inhibitor–induced apoptosis through the generation of reactive oxygen species

Department of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, Va

Read at the Eighty-fourth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, April 25-28, 2004.

Received for publication April 24, 2004; revisions received June 18, 2004; accepted for publication July 2, 2004.

^* 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).

OBJECTIVES: The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis in some malignancies through mitochondrial injury and generation of reactive oxygen species. Histone deacetylase inhibitors also activate the antiapoptotic transcription factor nuclear factor B. We hypothesize that proteasome inhibition with bortezomib (Velcade; Millennium Pharmaceuticals, Inc, Cambridge, Mass)will inhibit nuclear factor B activation, enhance suberoylanilide hydroxamic acid–induced mitochondrial injury, and sensitize non–small cell lung cancer cells to apoptosis.

METHODS: Four tumorigenic non–small cell lung cancer cell lines were treated with nothing, suberoylanilide hydroxamic acid, bortezomib, or both drugs. Nuclear factor B–dependent transcription was determined by reporter gene assays and endogenous interleukin 8 transcription. Reactive oxygen species were quantified by using the fluorophore H₂DCFDA. Cell viability was determined on the basis of clonogenic survival, and apoptosis was measured by quantifying caspase-3 activity and DNA fragmentation. Apoptosis and cell-survival assays were repeated in similarly treated cells incubated in the presence or absence of N-acetyl cysteine. Statistical significance was determined by means of analysis of variance.

RESULTS: Suberoylanilide hydroxamic acid significantly enhanced interleukin 8 and nuclear factor B–dependent reporter gene transcription, and these effects were inhibited by bortezomib (P .01). Combined treatment with suberoylanilide hydroxamic acid and bortezomib induced greater reactive oxygen species generation, more apoptosis (P .02), and more cell death (P .001) than either drug alone. N-acetyl cysteine diminished the induction of apoptosis and enhanced cell survival (P .04).

CONCLUSIONS: Suberoylanilide hydroxamic acid and bortezomib synergistically induce reactive oxygen species generation in non–small cell lung cancer, and this plays a critical role in the induction of apoptosis after treatment. Combined treatment with suberoylanilide hydroxamic acid and bortezomib might be an effective treatment strategy for non–small cell lung cancer.

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