Mechanisms by Which the Antitumor Compound Di-n-Butyl-Di-(4-Chlorobenzohydroxamato)Tin(IV) Induces Apoptosis and the Mitochondrial-Mediated Signaling Pathway in Human Cancer SGC-7901 Cells
Mechanisms by Which the Antitumor Compound Di-n-Butyl-Di-(4-Chlorobenzohydroxamato)Tin(IV) Induces Apoptosis and the Mitochondrial-Mediated Signaling Pathway in Human Cancer SGC-7901 Cells
复制标题
抗肿瘤化合物二正丁基二-(4-氯苯氧肟基)锡(IV)诱导人癌症SGC-7901细胞凋亡的机制及线粒体介导的信号通路
DOI：
10.1002/mc.20623
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发表时间：
2010-06-01
影响因子：
4.6
通讯作者：
Li, Qingshan
中科院分区：
文献类型：
--
作者：
Li, Yunlan;Liu, Jinjie;Li, Qingshan
本文首次研究了具有较强抗肿瘤活性的二有机锡化合物二正丁基二（4-氯苯并异羟肟酸）锡（DBDCT）诱导人胃癌细胞SGC-7901凋亡的机制。采用MTT法、流式细胞术、RT-PCR、Western blot、DNA Ladder、电镜和免疫细胞化学等方法检测4株肝癌细胞株与正常人肝L-O2细胞相比的增殖抑制、凋亡及相关mRNA和蛋白的表达。DBDCT可剂量依赖性和时间依赖性地降低胃癌细胞的增殖率，改变胃癌细胞的周期分布，使G（0）- G（1）期细胞比例增加，S期和G（2）- M期细胞比例减少。细胞周期阻滞可能与p21、p27、p53蛋白表达增加及增殖细胞核抗原（PCNA）表达降低有关。细胞凋亡的特征是DNA片段化，染色体浓缩，凋亡小体，亚G（1）峰，和增加的凋亡率，如使用annexin V-FITC方法所示。用N-乙酰半胱氨酸和caspase-9抑制剂预处理细胞可以减轻生长抑制和DBDCT诱导的凋亡。结果表明，DBDCT介导的细胞周期阻滞可能是通过以p53依赖的方式诱导p21而发生的，并且DBDCT诱导线粒体凋亡信号通路可能是通过增加Bax/Bcl-2比率介导的，这导致Delta Psi（m）的损失，细胞色素c释放到细胞质中，caspase-3和-9的激活，和增加的活性氧（ROS）产生。(C)2010 Wiley-Liss，Inc.
The mechanisms by which the strong antitumor diorganotin(IV) compound di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) (DBDCT) induces apoptosis of SGC-7901 cells were first investigated. Inhibition of proliferation of four cancer cell lines compared with normal human hepatic L-O2 cells, cancer cell apoptosis, and expression of related mRNA and protein were detected using the methyl thiazolyl tetrazolium (MTT), flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), Western blot, and DNA ladder assays, and electron microscopy and immunocytochemistry. DBDCT decreased cancer cell proliferation rates in a dose- and time-dependent manner and changed the cycle distribution of SGC-7901 cells; the proportion of cells in G(0) - G(1) phase was increased, whereas the numbers in S and G(2) - M phases were decreased. Blockade of the cell cycle was perhaps associated with increased levels of p21, p27, p53 and the decreased level of proliferating cell nuclear antigen (PCNA). Apoptosis was characterized by DNA fragmentation, chromosomal condensation, apoptotic bodies, sub-G(1) peaks, and an increased apoptotic rate, as shown using the annexin V-FITC method. Pretreatment of cells with N-acetylcysteine and caspase-9 inhibitor could reduce growth inhibition and DBDCT-induced apoptosis. The results showed that DBDCT-mediated cell-cycle arrest might occur through the induction of p21 in a p53-dependent manner and that DBDCT induction of the mitochondrial apoptotic signaling pathway is perhaps mediated by increasing Bax/Bcl-2 ratios, which result in the loss of Delta Psi(m), release of cytochrome c into the cytoplasm, activation of caspase-3 and -9, and increased reactive oxygen species (ROS) generation. (C) 2010 Wiley-Liss, Inc.