Received for publication August 29, 2007.
Revised December 20, 2007.
Accepted for publication December 20, 2007.

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

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 employed 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 (NSCLC) cells, primarily via enhanced collapse of the mitochondrial membrane potential, release of cytochrome c, and caspase activation. Furthermore, sulindac/SAHA co-treatment induced marked downregulation 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, while suppression of survivin levels with antisense oligonucleotides or small interfering RNA (siRNA) further sensitized cells to sulindac/SAHA-induced cell death. Our results collectively demonstrate that sulindac/SAHA-induced apoptosis is mediated by ROS-dependent downregulation of survivin in lung cancer cells.

Key words: Regulation of gene expression, Apoptosis