PT - JOURNAL ARTICLE AU - Sung-Keum Seo AU - Hyeon-Ok Jin AU - Hyung-Chahn Lee AU - Sang-Hyeok Woo AU - Eun-Sung Kim AU - Doo-Hyun Yoo AU - Su-Jae Lee AU - Sungkwan An AU - Chang-Hun Rhee AU - Seok-Il Hong AU - Tae-Boo Choe AU - In-Chul Park TI - Combined Effects of Sulindac and Suberoylanilide Hydroxamic Acid on Apoptosis Induction in Human Lung Cancer Cells AID - 10.1124/mol.107.041293 DP - 2008 Mar 01 TA - Molecular Pharmacology PG - 1005--1012 VI - 73 IP - 3 4099 - http://molpharm.aspetjournals.org/content/73/3/1005.short 4100 - http://molpharm.aspetjournals.org/content/73/3/1005.full SO - Mol Pharmacol2008 Mar 01; 73 AB - 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. The American Society for Pharmacology and Experimental Therapeutics