國家衛生研究院 NHRI:Item 3990099045/2700
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    題名: Mitochondria-mediated and p53-associated apoptosis induced in human cancer cells by a novel selenophene derivative, D-501036
    作者: Shiah, HS;Lee, WS;Juang, SH;Hong, PC;Lung, CC;Chang, CJ;Chou, KM;Chang, FY
    貢獻者: National Institute of Cancer Research
    摘要: D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrol], a novel selenophene derivative, is a highly potent cytotoxic agent with broad spectrum antitumor activity. The present study was undertaken to explore the mechanism(s) through which D501036 exerts its action mode on the cancer cell death. D-501036 was found to suppress the growth of KB and HepG(2) cells in an irreversible manner. The results of annexin-V assays and PARP cleavage studies were consistent with the D-501036-induced apoptosis. Findings provided a strong support for the induction of mitochondria-mediated apoptosis by this drug. The examination of two canonical pathways of initiation caspases, those for caspases -8 and -9, revealed that caspase-9 protein and the activities of caspases -9 and -3 were increased in a dose- and time-dependent manner. The concentrations of Fas/Fas-L and procaspase-8 and the activity of caspase-8 were not altered. Furthermore, the mitochondrial membrane potential permeability and the release of cytochrome c to the cytosol were both increased by D-501036. The concentrations of the pro-apoptotic protein Bax and translocation of Bax from the cytosol to the mitochondria were increased in response to D-501036, whereas the concentrations of the anti-apoptotic protein Bcl-2 were decreased. Two DNA damage-related pro-apoptotic proteins, Puma and Noxa, were upregulated in a dose- and time-dependent manner. These pro-apoptotic and anti-apoptotic proteins are downstream effectors of p53. Accordingly, the phosphorylated and total forms of p53 were induced and p53 was translocated from the cytosol to the mitochondria in response to D-501036 treatment. Collectively, we conclude that D-501036 induces cellular apoptosis through the p53-associated mitochondrial pathway. (c) 2006 Published by Elsevier Inc.
    關鍵詞: Pharmacology & Pharmacy
    日期: 2007-03-01
    關聯: Biochemical Pharmacology. 2007 Mar;73(5):610-619.
    Link to: http://dx.doi.org/10.1016/j.bcp.2006.10.019
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0006-2952&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000244380100002
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33846518865
    顯示於類別:[夏和雄(1996-2012)] 期刊論文
    [張俊彥] 期刊論文

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