Synergistic induction of apoptosis by sulindac and arsenic trioxide in human lung cancer A549 cells via reactive oxygen species-dependent down-regulation of survivin

• Published in: Biochemical pharmacology 2006-11, Vol.72 (10), p.1228-1236
• Main Authors: Jin, Hyeon-Ok, Yoon, Su-Im, Seo, Sung-Keum, Lee, Hyung-Chahn, Woo, Sang-Hyeok, Yoo, Doo-Hyun, Lee, Su-Jae, Choe, Tae-Boo, An, Sungkwan, Kwon, Tae-Jong, Kim, Jong-Il, Park, Myung-Jin, Hong, Seok-Il, Park, In-Chul, Rhee, Chang-Hun
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Arsenic trioxide; Arsenicals - administration & dosage; Arsenicals - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Down-Regulation; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Lung cancer; Lung Neoplasms - pathology; Medical sciences; Microtubule-Associated Proteins - biosynthesis; Neoplasm Proteins - biosynthesis; NSAIDs; Oxides - administration & dosage; Oxides - pharmacology; Pharmacology. Drug treatments; Pneumology; Reactive Oxygen Species - metabolism; Sulindac - administration & dosage; Sulindac - pharmacology; Survivin; Tumors of the respiratory system and mediastinum
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2006.07.026

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.