Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells
Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells
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DOI：
10.1016/j.ejphar.2006.11.010
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发表时间：
2007-02-14
影响因子：
5
通讯作者：
Los, Marek
中科院分区：
文献类型：
--
作者：
Hashemi, Mohammad;Ghavami, Saeid;Los, Marek
锌是一种必需的微量元素，在许多蛋白质的中间代谢、激素分泌途径、免疫防御机制中具有辅因子作用，作为转录因子的辅因子也参与了基因表达的调控。我们的研究表明，仅细胞内和细胞外锌的调节就足以诱导两个模型人乳腺癌细胞株MCF-7和MDA-MB468的代谢变化甚至凋亡。用不同浓度的细胞膜通透性锌络合剂N，N，N‘N’-四(2-吡啶甲基)乙二胺(TPEN)和膜不通透性锌络合剂二乙基三氨基五乙酸(DTPA)处理乳腺癌细胞后，细胞死亡明显增加。DTPA和TPEN诱导的细胞死亡伴随着染色质凝集和核碎裂等细胞凋亡特征。Caspase-9活性在两种细胞系中均显著升高，而caspase-3活性仅在MDA-MB468细胞中增强，因为caspase-3在MCF-7细胞中不表达。在这两种细胞系中，caspase-8的激活都可以忽略不计。添加锌或铜离子可阻止DTPA和TPEN诱导的细胞毒性，表明在我们的实验体系中，这两种二价阳离子都可以在一定程度上被取代。有趣的是，添加Ca~(2+)或Mg~(2+)没有影响。抗氧化剂N-乙酰-L-半胱氨酸可抑制DTPA和TPEN的细胞毒作用，提示氧化应激可能是缺锌相关细胞死亡的介质。(C)2006爱思唯尔B.V.保留所有权利。
Zinc is an essential trace element with cofactor functions in a large number of proteins of intermediary metabolism, hormone secretion pathways, immune defence mechanisms, and as a cofactor of transcription factors it is also involved in the control of gene expression. Our study demonstrates that the modulation of intra and extracellular zinc alone is sufficient to induce metabolic changes or even apoptosis in two model human breast cancer cell lines MCF-7 and MDA-MB468. Treatment of breast cancer cells with different concentrations of a cell membrane permeable zinc chelator, N,N,N'N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and the membrane impermeable zinc chelator, diethylenctriaminepentacetic acid, (DTPA) resulted in a significant increase of cell death. Features of apoptosis, such as chromatin condensation and nuclear fragmentation accompanied the DTPA and TPEN-induced cell death. A significant increase in the activity of caspase-9 was observed in both cell lines; whereas, caspase-3 activity was only increased in MDA-MB468 cells since caspase-3 is not expressed in MCF-7 cells. Caspase-8 activation was negligible in both cell lines. Addition of Zn2+ or Cu2+ prevented DTPA and TPEN-induced cytotoxicity, indicating that both bivalent cations can be replaced functionally to a certain extent in our experimental system. Interestingly, addition of Ca2+, or Mg2+ had no effect. The antioxidant N-Acetyl-L-Cysteine inhibited the cytotoxic effect of DTPA and TPEN, indicating that oxidative stress is the likely mediator of Zn-deficiency-related cell death. (c) 2006 Elsevier B.V. All rights reserved.