1. Synergistic induction of apoptosis by sulindac and arsenic trioxide in human lung cancer A549 cells via reactive oxygen species-dependent down-regulation of survivin
- Author
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Su-Im Yoon, Tae-Jong Kwon, Tae-Boo Choe, Seok-Il Hong, In-Chul Park, Hyung-Chahn Lee, Sung-Keum Seo, Doo-Hyun Yoo, Sang-Hyeok Woo, Jong-Il Kim, Myung-Jin Park, Sungkwan An, Chang-Hun Rhee, Su-Jae Lee, and Hyeon-Ok Jin
- Subjects
Programmed cell death ,Lung Neoplasms ,Cell Survival ,Survivin ,Down-Regulation ,Apoptosis ,Inhibitor of apoptosis ,Biochemistry ,Arsenicals ,Inhibitor of Apoptosis Proteins ,chemistry.chemical_compound ,Sulindac ,Arsenic Trioxide ,Cell Line, Tumor ,medicine ,Humans ,Arsenic trioxide ,Pharmacology ,A549 cell ,Drug Synergism ,Oxides ,digestive system diseases ,Neoplasm Proteins ,XIAP ,chemistry ,Cancer research ,Reactive Oxygen Species ,Microtubule-Associated Proteins ,medicine.drug - Abstract
Survivin, a member of the inhibitor of apoptosis protein (IAP) family, may be a good target for cancer therapy because it is expressed in a variety of human tumors but not in differentiated adult tissues. In the present study, we show that a combination of sulindac and arsenic trioxide (ATO) induces more extensive apoptosis than either drug alone in A549 human non-small cell lung carcinoma (NSCLC) cells. Treatment with sulindac/ATO reduced the expression of survivin and promoted major apoptotic signaling events, namely, collapse of the mitochondrial membrane potential, release of cytochrome c, and activation of caspases. Combined sulindac/ATO treatment did not significantly affect the levels of other members of the IAP family (XIAP, cIAP1 and cIAP2), indicating that the effects were specific to survivin. In addition, sulindac/ATO treatment induced the production of reactive oxygen species and the antioxidant N-acetyl-l-cysteine blocked the down-regulation of survivin and induction of apoptotic signaling by the combination of sulindac and ATO. Combined sulindac/ATO treatment also activated p53 expression, and inhibition of p53 expression by small interfering RNA (siRNA) prevented sulindac/ATO-induced down-regulation of survivin, suggesting that survivin expression is negatively regulated by p53. Overexpression of survivin reduced sulindac/ATO-induced apoptosis in A549 cells and reduction of survivin levels by siRNA sensitized the cells to sulindac/ATO-induced cell death. These results demonstrate that, in A549 human NSCLC cells, sulindac/ATO-induced apoptosis is mediated by the reactive oxygen species-dependent down-regulation of survivin.
- Published
- 2006