國家衛生研究院 NHRI:Item 3990099045/6102
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    題名: BPR1K653, a novel Aurora Kinase Inhibitor, exhibits potent anti-proliferative activity in P-gp170 (MDR1)-mediated VX680-resistant cancer cells in vitro and in vivo
    作者: Hsieh, HP;Cheung, CHA;Lin, WH;Hsu, TA;Coumar, MS;Chao, YS;Chang, JY
    貢獻者: Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research
    摘要: Background: Mitosis is a key step in cell cycle that is tightly regulated by many proteins. Abnormal expression or activation of these regulatory proteins could result in aberrant mitosis, leading to the development of cancer [1]. At the molecular level, Aurora kinases (Aurora-A, Aurora-B and Aurora-C) are serine/threonine kinases that function as key regulators of mitosis. In this study, a novel pan-Aurora kinase inhibitor entitled BPR1K653 was developed and its potency against various MDR1-negative and MDR1-positive cancer cells was evaluated. Our data revealed that unlike the well characterized Aurora kinase inhibitors VX680 and PHA-739358, BPR1K653 is effective in targeting both MDR1-negative and -positive cancer cells in vitro and in vivo. Materials and Methods: In vitro kinase activity assay was used to determine the activity and target specificity of BPR1K653. Antiproliferative activity of BPR1K653 was evaluated in various cancer cell lines. Flow cytomertic analysis, immunofluorescence microscopy, Western blot analysis, real-time caspase?3/?7 activity imaging, and the TUNEL assay were used to follow mechanisms of action of BPR1K653. Efficacy of BPR1K653 was determined in different xenograft mice models. Results: BPR1K653 specifically inhibited the activity of Aurora-A/-B kinase in vitro. It showed potent activity in a variety of human tumour cell lines regardless to the tissue origin, p53 status, and expression of the common drug efflux pump MDR1 (P-gp-170). In contrast, clinically tested Aurora kinase inhibitors, VX680 and PHA-739358, were ineffective in targeting the MDR1-expressing cancer cells. Interestingly, MDR1-expressing cancer cells treated with BPR1K653, but not with VX680, showed reduced-MDR1 activity. BPR1K653 induced cell endo-replication and the reduction of phosphor-histone H3, which are classical phenotypes of Aurora kinase inhibition. BPR1K653 also showed potent activity against the growth of xenograft tumours of the human cervical carcinoma KB and KB-derived MDR1-expressing VX680/vincristine-resistant KB-VIN10 cells in nude mice. Conclusion: BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.
    日期: 2011-09-23
    關聯: European Journal of Cancer. 2011 Sep 23;47:S127.
    Link to: http://dx.doi.org/10.1016/S0959-8049(11)70753-5
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0959-8049&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000295752800447
    顯示於類別:[謝興邦] 會議論文/會議摘要
    [趙宇生(2002-2013)] 會議論文/會議摘要
    [張俊彥] 會議論文/會議摘要
    [徐祖安] 會議論文/會議摘要

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