Downregulation of XIAP and induction of apoptosis by the synthetic cyclin-dependent kinase inhibitor GW8510 in non-small cell lung cancer cells

Small-molecule inhibitors of cyclin-dependent kinases (CDKs) are known to induce cell cycle arrest and apoptosis in certain cancer cells. In order to evaluate the antitumor activity of one such inhibitor, GW8510, against human lung cancers, we analyzed the effects of GW8510 on six non-small cell lun...

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Bibliographic Details
Published in:Cancer biology & therapy 2006-02, Vol.5 (2), p.165-170
Main Authors: Dong, Fengqin, Guo, Wei, Zhang, Lidong, Wu, Shuhong, Teraishi, Fuminori, Davis, John J., Fang, Bingliang
Format: Article
Language:English
Subjects:
Apoptosis
Binding
Biology
Bioscience
Calcium
Cancer
Carcinoma, Non-Small-Cell Lung - drug therapy
Cell
Cycle
Cyclin-Dependent Kinases - antagonists & inhibitors
Down-Regulation
Humans
Indoles - therapeutic use
Landes
Lung Neoplasms - drug therapy
Organogenesis
Proteins
RNA, Messenger - metabolism
Transcription, Genetic - drug effects
X-Linked Inhibitor of Apoptosis Protein - genetics
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Summary:Small-molecule inhibitors of cyclin-dependent kinases (CDKs) are known to induce cell cycle arrest and apoptosis in certain cancer cells. In order to evaluate the antitumor activity of one such inhibitor, GW8510, against human lung cancers, we analyzed the effects of GW8510 on six non-small cell lung cancer (NSCLC) cell lines (A549, H1299, H460, H226, H358, and H322) and normal human fibroblast (NHFB). We treated the cells with GW8510 at concentrations of 0-10 μM, and found that it suppressed cell growth in vitro in all the lung cancer cells but not in NHFB. Subsequent study showed that GW8510 induced apoptosis and cell cycle arrest in the A549, H1299 and H460 cells in a time- and dose-dependent manner. Western blot analysis showed that GW8510 downregulated the expression of X-linked inhibitor of apoptosis (XIAP) but had no detectable effect on the expression of Bax, Bak, or Bcl2. GW8510 also downregulated XIAP mRNA level, suggesting that downregulation of XIAP expression occurs at the transcriptional level. Moreover, ectopic XIAP expression diminished growth inhibition and apoptosis induction by GW8510. Importantly, GW8510 was not capable of inducing apoptosis of NHFB cells. These results suggest that GW8510 might provide a treatment strategy for human NSCLC and XIAP is an important target for GW8510-induced apoptosis of NSCLC cells that occurs through inhibition of XIAP mRNA transcription.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.5.2.2316