Pre-clinical antitumour evaluation of Biphosphinic Palladacycle Complex in human leukaemia cells
Pre-clinical antitumour evaluation of Biphosphinic Palladacycle Complex in human leukaemia cells
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DOI：
10.1016/j.cbi.2008.10.034
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发表时间：
2009-02-12
影响因子：
5.1
通讯作者：
Bincoletto, Claudia
中科院分区：
文献类型：
--
作者：
Oliveira, Carlos R.;Barbosa, Christiano M. V.;Bincoletto, Claudia
本课题组在前期的研究中发现了一种新的抗肿瘤药物，称为双膦钯络合物（Biphosphinic Palladacetate Complex，BPC）。在本文中，我们表明，BPC引起白血病细胞（HL 60和Jurkat）的凋亡，但不是在正常的人淋巴细胞。在BPC处理后5小时，使用MTT和台盼蓝排除试验获得的两种细胞系的IC 50值均低于8.0 μ M。利用异染荧光团吖啶橙子，我们观察到BPC引起白血病细胞的溶酶体破裂。此外，BPC在细胞系中触发caspase-3和caspase-6活化和凋亡，诱导染色质凝聚、凋亡小体和DNA片段化。有趣的是，溶酶体组织蛋白酶B抑制剂CA 074显著降低了DPC诱导的caspase-3和caspase-6活化以及细胞死亡。溶酶体BPA诱导的膜不稳定不依赖于活性氧的产生，这与细胞HL 60和Jurkat膜脂质过氧化的情况下是一致的。我们的结论是，BPC治疗后，溶酶体膜破裂之前的细胞死亡和细胞凋亡信号通路是由组织蛋白酶B在白血病细胞的细胞质中的释放。由于没有观察到对人淋巴细胞的毒性作用，我们认为BPC对转化细胞更具选择性，这主要是由于它们的溶酶体表达加剧。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Previous studies reported by Our group have introduced a new antitumoural drug called Biphosphinic Palladacycle Complex (BPC). In this paper we show that BPC causes apoptosis in leukaemia cells (HL60 and Jurkat), but not in normal human lymphocytes. IC50 values obtained for both cell lines using the MTT and trypan blue exclusion assays 5 h after BPC treatment were lower than 8.0 mu M. Using metachromatic fluorophore, acridine orange, we observed that BPC elicited lysosomal rupture of leukaemic cells. Furthermore, BPC triggered caspase-3 and caspase-6 activation and apoptosis in cell lines, inducing chromatin condensation, apoptotic bodies, and DNA fragmentation. Interestingly, the lysosomal cathepsin B inhibitor CA074 markedly decreased BPC-induced caspase-3 and caspase-6 activation as well as cell death. Lysosomal BPC-induced membrane destabilisation was not dependent on reactive oxygen species generation, which was consistent with the absence of cellular HL60 and Jurkat membrane lipid peroxidation. We conclude that, following BPC treatment, lysosomal membrane rupture precedes cell death and the apoptotic signalling pathway is initiated by the release of cathepsin B in the cytoplasm of leukaemia cells. As no toxic effects for human lymphocytes were observed, we suggest that BPC is more selective for transformed cells, mainly due to their exacerbated lysosome expression. (C) 2008 Elsevier Ireland Ltd. All rights reserved.