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http://ir.nhri.org.tw/handle/3990099045/2700
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| Title: | Mitochondria-mediated and p53-associated apoptosis induced in human cancer cells by a novel selenophene derivative, D-501036 |
| Authors: | Shiah, HS;Lee, WS;Juang, SH;Hong, PC;Lung, CC;Chang, CJ;Chou, KM;Chang, FY |
| Contributors: | National Institute of Cancer Research |
| Abstract: | 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. |
| Keywords: | Pharmacology & Pharmacy |
| Date: | 2007-03-01 |
| Relation: | 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 |
| Appears in Collections: | [夏和雄(1996-2012)] 期刊論文
[張俊彥] 期刊論文
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| 000244380100002.pdf | | 816Kb | Adobe PDF | 1107 | View/Open |
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