國家衛生研究院 NHRI:Item 3990099045/5266
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/5266


    Title: Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints
    Authors: Wang, HH;Cheng, KC;Lin, CJ;Hsu, SW;Fang, WC;Hsu, TF;Chiu, CC;Chang, HH;Hsu, CH;Lee, AYL
    Contributors: National Institute of Cancer Research
    Abstract: Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and ())-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzymebased screening, we identified two small-molecule compounds, obtusilactone A (OA) and ())-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and ())-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and ())-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G1 ⁄ S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G1 accumulation. In conclusion, OA and ())-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA
    damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics.
    Date: 2010-12
    Relation: Cancer Science. 2010 Dec;101(12):2612-2620.
    Link to: http://dx.doi.org/10.1111/j.1349-7006.2010.01701.x
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1347-9032&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000284321300019
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=78449276275
    Appears in Collections:[Alan Yueh-Luen Lee] Periodical Articles

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