Synergistic induction of apoptosis by sulindac and arsenic trioxide in human lung cancer A549 cells via reactive oxygen species-dependent down-regulation of survivin.
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.
Jin
Hyeon-Ok
HO
Laboratory of Functional Genomics, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-Dong, Nowon-Gu, Seoul, Republic of Korea.
Yoon
Su-Im
SI
Seo
Sung-Keum
SK
Lee
Hyung-Chahn
HC
Woo
Sang-Hyeok
SH
Yoo
Doo-Hyun
DH
Lee
Su-Jae
SJ
Choe
Tae-Boo
TB
An
Sungkwan
S
Kwon
Tae-Jong
TJ
Kim
Jong-Il
JI
Park
Myung-Jin
MJ
Hong
Seok-Il
SI
Park
In-Chul
IC
Rhee
Chang-Hun
CH
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013467:Sulindac / Q000008:administration & dosage / Q000494:pharmacology*; D000077022:Survivin
D001152:Arsenicals; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; D000077022:Survivin; D013467:Sulindac; D000077237:Arsenic Trioxide