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First published on December 21, 2007; DOI: 10.1124/mol.107.041293

0026-895X/08/7303-1005-1012$20.00
Mol Pharmacol 73:1005-1012, 2008

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Combined Effects of Sulindac and Suberoylanilide Hydroxamic Acid on Apoptosis Induction in Human Lung Cancer Cells

Sung-Keum Seo, Hyeon-Ok Jin, Hyung-Chahn Lee, Sang-Hyeok Woo, Eun-Sung Kim, Doo-Hyun Yoo, Su-Jae Lee, Sungkwan An, Chang-Hun Rhee, Seok-Il Hong, Tae-Boo Choe, and In-Chul Park

Laboratory of Radiation Resistance Control, Korea Institute of Radiological & Medical Sciences, Seoul, Korea (S.-K.S., H.-O.J., H.-C.L., S.-H.W., E.-S.K., D.-H.Y., I.-C.P.); Department of Neurosurgery, Korea Institute of Radiological & Medical Sciences, Seoul, Korea (C.-H.R.); Department of Clinical Pathology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea (S.-I.H.); Department of Microbiological Engineering, Kon-Kuk University, Seoul, Korea (S.-K.S., S.A., T.-B.C.); and Department of Chemistry, Han-Yang University, Seoul, Korea (S.-J.L.)

Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. Treatment of cancer cells with HDAC blockers, such as suberoylanilide hydroxamic acid (SAHA), leads to the activation of apoptosis-promoting genes. To enhance proapoptotic efficiency, SAHA has been used in conjunction with radiation, kinase inhibitors, and cytotoxic drugs. In the present study, we show that at the suboptimal dose of 250 µM, sulindac [2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]-acetic acid] significantly enhances SAHA-induced growth suppression and apoptosis of A549 human non-small cell lung cancer cells, primarily via enhanced collapse of the mitochondrial membrane potential, release of cytochrome c, and caspase activation. Furthermore, sulindac/SAHA cotreatment induced marked down-regulation of survivin at both the mRNA and protein levels and stimulated the production of reactive oxygen species (ROS), which were blocked by the antioxidant N-acetyl-L-cysteine. Overexpression of survivin was associated with reduced sulindac/SAHA-induced apoptosis of A549 cells, whereas suppression of survivin levels with antisense oligonucleotides or small interfering RNA further sensitized cells to sulindac/SAHA-induced cell death. Our results collectively demonstrate that sulindac/SAHA-induced apoptosis is mediated by ROS-dependent down-regulation of survivin in lung cancer cells.

Received August 28, 2007; accepted December 20, 2007

Address correspondence to: In-Chul Park, Ph.D. Laboratory of Radiation Resistance Control, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, 139-706 Nowon-Ku, Seoul, Korea. E-mail: parkic{at}kcch.re.kr






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