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標題: Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53
作者: Ho, T.F.
Ma, C.J.
Lu, C.H.
Tsai, Y.T.
Wei, Y.H.
Chang, J.S.
La, J.K.
Cheuh, P.J.
Yeh, C.T.
Tang, P.C.
Chang, J.H.T.
Ko, J.L.
Liu, F.S.
Yen, H.C.E.
Chang, C.C.
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.
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.
ISSN: 0041-008X
DOI: 10.1016/j.taap.2007.08.007
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