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KMID : 0613820090190081073
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Journal of Life Science
2009 Volume.19 No. 8 p.1073 ~ p.1080
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Combined Treatment of Nonsteroidal Anti-inflammatory Drugs and Genistein Synergistically Induces Apoptosis via Induction of NAG-1 in Human Lung Adenocarcinoma A549 Cells
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Kim Cho-Hee
Kim Min-Young
Lee Su-Yeon
Moon Ji-Young
Han Song-Iy
Park Hye-Gyeong
Kang Ho-Sung
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Abstract
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A number of studies have demonstrated that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risks of colorectal, oesophageal and lung cancers. NSAIDs have been shown to exert their anti-cancer effects through inducing apoptosis in cancer cells. The susceptibility of tumor cells to anti-tumor drug-induced apoptosis appears to depend on the balance between pro-apoptotic and anti-apoptotic programs such as nuclear factor kB (NF-kB), phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) and MEK1/2-ERK1/2 pathways. We examined the effects of pro-survival PI3K and ERK1/2 signal pathways on cell cycle arrest and apoptosis in response to NSAIDs including sulindac sulfide and NS398. We show that simultaneous inhibition of the Akt/PKB and ERK1/2 signal cascades could synergistically enhance the potential pro-apoptotic activities of sulindac sulfide and NS398. Similar enhancement was observed in cells treated with sulindac sulfide or NS398 and 100 μM genistein, an inhibitor of receptor tyrosine kinases (RTKs) that are upstream of PI3K and MEK1/2 signaling. We further demonstrate that NAG-1 is induced and plays a critical role(s) in apoptosis by NSAIDs-based combined treatment. In sum, our results show that combinatorial treatment of sulindac sulfide or NS398 and genistein results in a highly synergistic induction of apoptotic cell death to increase the chemopreventive effects of the NSAIDs, sulindac sulfide and NS398.
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KEYWORD
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Sulindac, NS398, genistein, apoptosis, PI3K, ERK1/2, NAG-1
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