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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/27764


    標題: A Synthetic Podophyllotoxin Derivative Exerts Anti-Cancer Effects by Inducing Mitotic Arrest and Pro-Apoptotic ER Stress in Lung Cancer Preclinical Models
    作者: Chen, Jia-Yang
    Tang, Yen-An
    Li, Wen-Shan
    Chiou, Yu-Ching
    Shieh, Jiunn-Min
    Wang, Yi-Ching
    貢獻者: 藥學系
    關鍵字: Antimitotic Activity
    Natural-Products
    Binding Agents
    Drug Discovery
    Resistance
    Tubulin
    Mitosis
    Microtubules
    Expression
    Kinases
    日期: 2013-04
    上傳時間: 2014-05-26 10:42:43 (UTC+8)
    出版者: Public Library Science
    摘要: Some potent chemotherapy drugs including tubulin-binding agents had been developed from nature plants, such as podophyllotoxin and paclitaxel. However, poor cytotoxic selectivity, serious side-effects, and limited effectiveness are still the major concerns in their therapeutic application. We developed a fully synthetic podophyllotoxin derivative named Ching001 and investigated its anti-tumor growth effects and mechanisms in lung cancer preclinical models. Ching001 showed a selective cytotoxicity to different lung cancer cell lines but not to normal lung cells. Ching001 inhibited the polymerization of microtubule resulting in mitotic arrest as evident by the accumulation of mitosis-related proteins, survivin and aurora B, thereby leading to DNA damage and apoptosis. Ching001 also activated pro-apoptotic ER stress signaling pathway. Intraperitoneal injection of 2 mg/kg Ching001 significantly inhibited the tumor growth of A549 xenograft, while injection of 0.2 mg/kg Ching001 decreased the lung colonization ability of A549 cells in experimental metastasis assay. These anti-tumor growth and lung colonization inhibition effects were stronger than those of paclitaxel treatment at the same dosage. The xenograft tumor tissue stains further confirmed that Ching001 induced mitosis arrest and tumor apoptosis. In addition, the hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. We provided preclinical evidence that novel synthetic microtubule inhibitor Ching001, which can trigger DNA damage and apoptosis by inducing mitotic arrest and ER stress, is a potential anti-cancer compound for further drug development.
    Appears in Collections:[藥學系(所)] 期刊論文

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