Role of cell cycle events and apoptosis in mediating the anti-cancer activity of a silver(I) complex of 4-hydroxy-3-nitro-coumarin-bis(phenanthroline) in human malignant cancer cells
Role of cell cycle events and apoptosis in mediating the anti-cancer activity of a silver(I) complex of 4-hydroxy-3-nitro-coumarin-bis(phenanthroline) in human malignant cancer cells
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DOI：
10.1016/j.ejphar.2008.11.020
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发表时间：
2009-01-14
影响因子：
5
通讯作者：
Egan, Denise A.
中科院分区：
文献类型：
--
作者：
Thati, Bhumika;Noble, Andy;Egan, Denise A.
本研究的主要目的是使用四种人源性模型细胞系研究4-羟基-3-硝基香豆素（hncH）和4-氧-3-硝基香豆素-双（菲咯啉）的混合配体银（I）配合物[Ag（hnc）（phen）（2）]的潜在体外抗增殖作用。此外，使用四种细胞系中最敏感的细胞系进行了选定的机制研究。结果表明，该复合物可抑制所有四种细胞系的增殖，包括肾肿瘤细胞系A-498和肝肿瘤细胞系HepG（2），沿着的还有两种非肿瘤细胞系HK-2和Chang。此外，非肿瘤性肝细胞（Chang）似乎对复合物的作用不太敏感，但这种作用在非肿瘤性肾细胞（HK-2）中没有复制。基于IC 50值，使用HePG（2）细胞，显示[Ag（hnc）（phen）（2）]的效力几乎是顺铂的4倍。此外，观察到的抗增殖作用显示为剂量和时间依赖性。此外，复合物被证明可以减少DNA合成，但不嵌入它。此外，没有证据表明P-糖蛋白介导的多药耐药可能会降低抗增殖活性。细胞学染色、基因组DNA分析和生物化学测定[半胱天冬酶-3和-9和裂解的聚（ADP-核糖）聚合酶蛋白]表明，细胞死亡似乎是由细胞凋亡引起的，并可能发生继发性坏死。此外，流式细胞术分析表明，该复合物通过改变细胞周期进程发挥作用。总之，[Ag（hnc）（phen）（2）]已被证明是比顺铂更有效的抗增殖剂，能够改变导致细胞死亡的关键生化事件。其他机制研究正在进行中，以更全面地探讨其作用机制。(C)2008 Elsevier B. V.保留所有权利。
The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of 4-hydroxy-3-nitro-coumarin (hncH), and the mixed-ligand silver (I) complex of 4-oxy-3-nitro-coumarin-bis (phenanthroline), [Ag(hnc)(phen)(2)] using four human-derived model cell lines. In addition, selected mechanistic studies were carried out using the most sensitive of the four cell lines. Results obtained show that the complex could decrease the proliferation of all four cell lines including neoplastic renal and hepatic, namely A-498 and HepG(2) cells, respectively, along with two non-neoplastic renal and hepatic cell lines, HK-2 and Chang, respectively. Furthermore, non-neoplastic hepatic cells (Chang) appeared to be less sensitive to the effect of the complex, but this effect was not replicated in the non-neoplastic renal (HK-2) cells. Based on IC50 values [Ag(hnc)(phen)(2)] was shown to be almost four times more potent than cisplatin, using HePG(2) cells. In addition, the observed anti-proliferative effect was shown to be both dose- and time-dependent. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Moreover, there was no evidence that P-glycoprotein-mediated multi-drug resistance was likely to decrease antiproliferative activity. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein] showed that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Ag(hnc)(phen)(2)] has been shown to be a more potent anti-proliferative agent than cisplatin, capable of altering key biochemical events leading to cell death. Additional mechanistic studies are underway to probe more fully its mechanism of action. (C) 2008 Elsevier B.V. All rights reserved.