Hashemi Mohammad, Ghavami Saeid, Eshraghi Mehdi, Booy Evan P, Los Marek
Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
Eur J Pharmacol. 2007 Feb 14;557(1):9-19. doi: 10.1016/j.ejphar.2006.11.010. Epub 2006 Nov 10.
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, diethylenetriaminepentacetic 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 Zn(2+) or Cu(2+) 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 Ca(2+), or Mg(2+) 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.
锌是一种必需的微量元素，在大量参与中间代谢的蛋白质、激素分泌途径、免疫防御机制中发挥辅助因子的作用，并且作为转录因子的辅助因子，它还参与基因表达的调控。我们的研究表明，单独调节细胞内和细胞外的锌就足以在两种人乳腺癌细胞系MCF-7和MDA-MB468中诱导代谢变化甚至凋亡。用不同浓度的细胞膜可渗透锌螯合剂N,N,N',N'-四(2-吡啶甲基)乙二胺(TPEN)和细胞膜不可渗透锌螯合剂二乙三胺五乙酸(DTPA)处理乳腺癌细胞，导致细胞死亡显著增加。凋亡特征，如染色质浓缩和核碎片化伴随着DTPA和TPEN诱导的细胞死亡。在两种细胞系中均观察到caspase-9活性显著增加；然而，caspase-3活性仅在MDA-MB468细胞中增加，因为MCF-7细胞中不表达caspase-3。在两种细胞系中caspase-8的激活可忽略不计。添加Zn(2+)或Cu(2+)可防止DTPA和TPEN诱导的细胞毒性，表明在我们的实验系统中，这两种二价阳离子在功能上可以在一定程度上相互替代。有趣的是，添加Ca(2+)或Mg(2+)没有效果。抗氧化剂N-乙酰-L-半胱氨酸抑制了DTPA和TPEN的细胞毒性作用，表明氧化应激可能是锌缺乏相关细胞死亡的介质。
