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|標題:||Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53||作者:||Ho, T.F.
|關鍵字:||undecylprodigiosin (UP);breast cancer;apoptosis;z-VAD.fmk;poly;(ADP-ribose) polymerase (PARP);Bcl-2 family;p53;nf-kappa-b;prodigiosin 25-c;bcl-2 family;cancer-cells;induction;death;proliferation;protein;gene;supplementation||Project:||Toxicology and Applied Pharmacology||期刊/報告no：:||Toxicology and Applied Pharmacology, Volume 225, Issue 3, Page(s) 318-328.||摘要:||
Undecylprodigiosin (UP) is a bacterial bioactive metabolite produced by Streptomyces and Serratia. In this study, we explored the anticancer effect of UP. Human breast carcinoma cell lines BT-20, MCF-7, MDA-MB-231 and T47D and one nonmalignant human breast epithelial cell line, MCF-10A, were tested in this study. We found that UP exerted a potent cytotoxicity against all breast carcinoma cell lines in a dose- and time-dependent manner. In contrast, UP showed limited toxicity to MCF-10A cells, indicating UP's cytotoxic effect is selective for malignant cells. UP's cytotoxic effect was due to apoptosis, as confirmed by positive TUNEL signals, annexin V-binding, caspase 9 activation and PAR-P cleavage. Notably, UP-induced apoptosis was blocked by the pan-caspase inhibitor z-VAD.fmk, further indicating the involvement of caspase activity. Moreover, UP caused a marked decrease of the levels of antiapoptotic BCL-X-L, Survivin and XIAP while enhancing the levels of proapoptotic BIK, BIM, MCL-1S and NOXA, consequently favoring induction of apoptosis. Additionally, we found that cells with functional p53 (MCF-7, T47D) or mutant p53 (BT-20, MDA-MB-231) were both susceptible to UP's cytotoxicity. Importantly, UP was able to induce apoptosis in MCF-7 cells with p53 knockdown by RNA interference, confirming the dispensability of p53 in UP-induced apoptosis. Overall, our results establish that UP induces p53-independent apoptosis in breast carcinoma cells with no marked toxicity to nonmalignant cells, raising the possibility of its use as a new chemotherapeutic drug for breast cancer irrespective of p53 status. (c) 2007 Elsevier Inc. All rights reserved.
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