國家衛生研究院 NHRI:Item 3990099045/7439
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    题名: MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1 alpha mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR
    其它题名: MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1α mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR
    作者: Cheng, YC;Liou, JP;Kuo, CC;Lai, WY;Shih, KH;Chang, CY;Pan, WY;Tseng, JT;Chang, JY
    贡献者: National Institute of Cancer Research
    摘要: Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1 alpha(HIF-1 alpha) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1 alpha mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-aryl-indoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G(2)-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1 alpha protein but also destabilized HIF-1 alpha mRNA. The mechanism of causing unstable of HIF-1 alpha mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1 alpha of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.
    日期: 2013-07
    關聯: Molecular Cancer Therapeutics. 2013 Jul;12(7):1202-1212.
    Link to: http://dx.doi.org/10.1158/1535-7163.mct-12-0778
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1535-7163&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000321492700006
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84880049488
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    [郭靜娟] 期刊論文

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