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Introduction
The major reactive oxygen species (ROS) are hydroxyl radical (•OH), superoxide anion (O2•−) and hydrogen peroxide (H2O2), which are involved in a variety of cellular events such as transcription factor activation and cell proliferation (1). ROS can also induce damage in cells and tissues via the oxidation of DNA, lipid and protein (2). Therefore, cells and tissues have various antioxidants and systems to control the excessive ROS level. Superoxide dismutase (SOD), which metabolizes superoxide anion (O2•−) to hydrogen peroxide (H2O2), is expressed as extracellular (ecSOD), intracellular (Cu/ZnSOD) and mitochondrial (MnSOD) isoforms (3). Glutathione (GSH) is a dominant non-protein antioxidant in cells and supplies electrons for glutathione peroxidase to detoxify H2O2 to O2 and H2O (4). GSH is important for cell cycle progression and apoptosis and it is also known to protect cells from toxic metabolites and oxidative stress (5,6). Thioredoxin (Trx) as a small protein contains cysteine residues (Cys 32 and Cys 35) in the active site and the residues exist as either a dithiol in the reduced form and a disulfide in the oxidized form (7). When Trx is oxidized, it is reduced back to dithiol by nicotinamide adenine dinucleotide phosphate (NADPH)-dependent Trx reductase (TrxR) (7). There are two isoforms of Trx; cytoplasmic (Trx1) and mitochondrial (Trx2) (8). Especially, Trx1 is overexpressed in many cancer cells including colorectal and breast cancer (9,10) and has been reported as responsible for cellular resistance to anticancer drugs (11).
Histone deacetylase (HDAC) is a class of enzyme that removes acetyl groups from lysine amino acid on histones, leading to the suppression of transcription (12). Deregulation of HDAC has been observed in malignant tissues, resulting in the inhibition of tumor suppressor genes, thereby allowing the expression of the malignant phenotypes (13). In addition, previous studies have demonstrated that HDAC activity is upregulated in many human cancers and suggested that the ways to inhibit HDAC activity can be a novel strategy in cancer therapeutics (14,15). Suberoylanilide hydroxamic acid (SAHA) is a potent HDAC inhibitor, that has been used for the treatment of cutaneous T-cell lymphoma (16). Accumulating evidence indicates that SAHA has effects on many biological functions such as cell...