Abstract
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.
Footnotes
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This work was supported by the National Nuclear R&D Program of the Ministry of Sciences and Technology, Seoul, Korea.
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ABBREVIATIONS: HDAC, histone deacetylase; SAHA, suberoylanilide hydroxamic acid; NSCLC, non-small cell lung cancer; siRNA, small interfering RNA; ROS, reactive oxygen species; NSAID, nonsteroidal anti-inflammatory drug; NAC, N-acetyl-l-cysteine; MTT, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; PI, propidium iodide; DCFH-DA, dichlorofluorescein diacetate; MMP, mitochondrial transmembrane potential; RT-PCR, reverse transcription-polymerase chain reaction; IAP, inhibitor of apoptosis protein; XIAP, X-linked inhibitor of apoptosis protein.
- Received August 28, 2007.
- Accepted December 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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