https://scholars.lib.ntu.edu.tw/handle/123456789/338569
標題: | Cytotoxicity and proteomics analyses of OSU03013 in lung cancer | 作者: | Tan, Yi-Hung Lee, Kung-Hsueh Lin, Topp Sun, Ying-Chieh Hsieh-Li, Hsiu Mei Juan, Hsueh-Fen Wang, Yi-Ching |
公開日期: | 三月-2008 | 卷: | 14 | 期: | 6 | 起(迄)頁: | 1823-1830 | 來源出版物: | Clinical Cancer Research | 摘要: | Purpose: Most lung cancer patients have some resistance to and suffer from side effects of conventional chemotherapy. Thus, identification of a novel anticancer drug with better target selectivity for lung cancer treatment is urgently needed. Experimental Design: In order to investigate whether OSU03013, a derivative of celecoxib, can be a potential drug for lung cancer treatment, we examined its cytotoxicity mechanisms by flow cytometry and phosphatidylserine staining in A549, CL1-1, and H1435 lung cancer cell lines, which are resistant to the conventional drug, cisplatin. In addition, we identified the affected proteins by proteomics and confirmed the selected proteins by Western blot analysis. We examined the interaction between OSU03013 and potential target protein by molecular modeling. Results: Our results indicated that OSU03013 had low-dose (1-4 μM) cytotoxicity in all lung cancer cell lines tested 48 hours post treatment. OSU03013 caused cell cycle G1 phase arrest and showed phosphatidylserine early apoptosis via endoplasmic reticulum stress. Several proteins such as heat shock protein 27, 70, and 90, CDC2, α-tubulin, annexin A3, cAMP-dependent protein kinase, glycogen synthase kinase 3-beta, and β-catenin were identified by proteomics and confirmed by Western blot. In addition, molecular modeling showed that OSU03013 competes with ATP to bind to cAMP-dependent protein kinase. Conclusions: We identified for the first time that OSU03013 inhibits cAMP-dependent protein kinase activity and causes dephosphorylation of glycogen synthase kinase 3-beta leading to β-catenin degradation, which is often overexpressed in lung cancer. Our molecular and proteomic results show the potential of OSU03013 as an anticancer drug for lung cancer. ? 2008 American Association for Cancer Research. |
URI: | http://europepmc.org/abstract/med/18347185 http://scholars.lib.ntu.edu.tw/handle/123456789/338569 |
DOI: | 10.1158/1078-0432.CCR-07-1806 | SDG/關鍵字: | adenosine triphosphate; alpha tubulin; antineoplastic agent; beta catenin; cisplatin; cyclic AMP dependent protein kinase; cyclin dependent kinase 1; glycerophosphoinositol inositolphosphodiesterase; glycogen synthase kinase 3; heat shock protein 27; heat shock protein 70; heat shock protein 90; osu 03013; phosphatidylserine; unclassified drug; apoptosis; article; cancer cell culture; cell cycle arrest; cell cycle G1 phase; controlled study; cytotoxicity; drug binding; drug interaction; endoplasmic reticulum stress; flow cytometry; human; human cell; lung cancer; molecular model; priority journal; protein analysis; protein targeting; proteomics; staining; Western blotting; Antineoplastic Agents; Apoptosis; Carcinoma; Cell Line; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases; Drug Evaluation, Preclinical; Endoplasmic Reticulum; Female; G1 Phase; Humans; Lung Neoplasms; Models, Biological; Models, Molecular; Proteomics; Pyrazoles; Sulfonamides |
顯示於: | 生命科學系 |
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