Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity
Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity
复制标题
DOI：
10.1371/journal.pone.0013131
复制
发表时间：
2010-10-04
期刊：
影响因子：
3.7
通讯作者：
Neamati, Nouri
中科院分区：
文献类型：
--
作者：
Millard, Melissa;Pathania, Divya;Neamati, Nouri
背景：最近，人们对开发选择性靶向线粒体的化合物用于治疗肿瘤产生了浓厚的兴趣。线粒体在细胞代谢和呼吸中的关键作用支持这种治疗原理。能量产生和代谢过程中的功能障碍导致对促凋亡刺激的反应减弱和ROS产生增加，这两者都与大多数人类癌症的发生和进展有关。基于MTT的高通量筛选超过10，000种药物样小分子的抗增殖活性鉴定了磷鎓盐TP 187，197和421的IC 50浓度在亚微摩尔范围内。TP治疗诱导细胞周期停滞的p53状态无关，通过分析碘化丙啶染色的细胞中的DNA含量。在人乳腺癌小鼠模型中，与溶媒或紫杉醇处理的小鼠相比，TP处理的小鼠显示出显著降低的肿瘤生长。TP治疗后未观察到毒性或器官损伤。TP 187处理的肿瘤组织切片的免疫组织化学染色显示细胞增殖减少和caspase-3裂解增加。利用类似物TP 421的荧光特性来评估TP化合物的亚细胞摄取，证明线粒体定位。线粒体摄取后，细胞耗氧量降低，线粒体超氧化物产生随之增加。来自600个靶抗体微阵列的结果的蛋白质组学分析表明TP化合物显著影响与生长和增殖相关的信号传导途径。通过我们对设计靶向癌细胞代谢、瓦尔堡效应和线粒体的化合物的持续兴趣，我们最近发现了一系列新的，含有三苯基膦部分的小分子化合物，其在一组癌细胞系以及人乳腺癌小鼠模型中显示出显著的活性。作用机制包括线粒体定位导致氧消耗减少、超氧化物产生增加和生长因子信号传导减弱。
Background: Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers.Methodology/Principal Findings: A high-throughput MTT-based screen of over 10,000 drug-like small molecules for antiproliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC50 concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation.Conclusions/Significance: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling.