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Ann Thorac Surg 2006;81:1034-1042
© 2006 The Society of Thoracic Surgeons

Original article: General thoracic

Effectiveness of Trichostatin A as a Potential Candidate for Anticancer Therapy in Non–Small-Cell Lung Cancer

Nishit K. Mukhopadhyay, PhD a , * , Ellen Weisberg, PhD b , David Gilchrist, BS a , Raphael Bueno, MD a , David J. Sugarbaker, MD a , Michael T. Jaklitsch, MD a

a Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
b Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Accepted for publication June 22, 2005.

* Address correspondence to Dr Mukhopadhyay, Division of Urology, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115 (Email: nmukhopadhyay{at}partners.org).

BACKGROUND: A well-known histone deacetylase inhibitor, trichostatin A, was applied to non–small-cell lung cancer cells to determine whether inhibition of histone deacetylase leads to the production of proteins that either arrest tumor cell growth or lead to tumor cell death.

METHODS: Trichostatin A (0.01 to 1.0 µmol/L) was applied to one normal lung fibroblast and four non–small-cell lung cancer lines, and its effect was determined by flow cytometry, annexin-V staining, immunoprecipitation, and Western blot analysis.

RESULTS: Trichostatin A demonstrated tenfold greater growth inhibition in all four non–small-cell lung cancer lines compared with normal controls, with a concentration producing 50% inhibition ranging from 0.01 to 0.04 µmol/L for the tumor cell lines and 0.7 µmol/L for the normal lung fibroblast line. Trichostatin A treatment reduced the percentage of cells in S phase (10% to 23%) and increased G1 populations (10% to 40%) as determined by flow cytometry. Both annexin-V binding assay and upregulation of the protein, gelsolin (threefold to tenfold), demonstrated that the tumor cells were apoptotic, whereas normal cells were predominantly in cell cycle arrest. Trichostatin A increased histone H4 acetylation and expression of p21 twofold to 15-fold without significant effect on p16, p27, CDK2, and cyclin D1.

CONCLUSIONS: Collectively, these data suggest that inhibition of histone deacetylation may provide a valuable approach for lung cancer treatment. We evaluated trichostatin A as a potential candidate for anticancer therapy in non–small-cell lung cancer.




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