Nucleolar targeting by platinum: p53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction.
Nucleolar targeting by platinum: p53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction.
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DOI：
10.1021/mp5006867
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发表时间：
2015-01-05
影响因子：
4.9
通讯作者：
Farrell NP
中科院分区：
文献类型：
--
作者：
Peterson EJ;Menon VR;Gatti L;Kipping R;Dewasinghe D;Perego P;Povirk LF;Farrell NP
TriplatinNC是II期临床抗癌药物BBR 3464的高正电荷、取代惰性衍生物。这种取代惰性配合物形成了一个独特的子集的多核铂配合物（PPC）通过非共价相互作用与DNA和其他生物分子相互作用。通过与细胞表面糖氨基聚糖的相互作用促进快速细胞进入，并且是PPC特有的机制。纳米二次离子质谱（nanoSIMS）显示细胞质和核仁区室，但不是细胞核内的快速分布。在这篇文章中，核仁定位的下游效应进行了描述。在人结肠癌细胞HCT 116中，47 S rRNA前体转录物的产生率在药物治疗后的早期事件中显著降低。rRNA的转录抑制之后是一个强大的G1期阻滞，并以p53非依赖性方式激活凋亡蛋白caspase-8，-9和-3和PARP-1。使用细胞同步化和流式细胞术，确定在G1期处理的细胞立即停滞，但在S期或G2期处理的细胞成功完成有丝分裂。处理后24小时，大多数细胞最终停滞在G1期，但近三分之一含有高度致密的DNA;这是一种与有丝分裂、衰老或凋亡无关的独特生物学特征。这种独特的效应反映了tRNA和DNA在无细胞系统中的有效缩合。TriplatinNC处理的DNA压缩和细胞凋亡的组合在铂抗性和/或p53突变或无效细胞系中赋予了惊人的活性。总之，我们的研究结果支持TriplatinNC的生物活性反映了降低的代谢失活（取代惰性化合物不与硫亲核试剂反应），高细胞积累和高亲和力非共价DNA结合的新后果，产生了新的概况和抗肿瘤复合物的结构-活性范式的进一步转变。
TriplatinNC is a highly positively charged, substitution-inert derivative of the phase II clinical anticancer drug, BBR3464. Such substitution-inert complexes form a distinct subset of polynuclear platinum complexes (PPCs) interacting with DNA and other biomolecules through noncovalent interactions. Rapid cellular entry is facilitated via interaction with cell surface glycosoaminoglycans and is a mechanism unique to PPCs. Nanoscale secondary ion mass spectrometry (nanoSIMS) showed rapid distribution within cytoplasmic and nucleolar compartments, but not the nucleus. In this article, the downstream effects of nucleolar localization are described. In human colon carcinoma cells, HCT116, the production rate of 47S rRNA precursor transcripts was dramatically reduced as an early event after drug treatment. Transcriptional inhibition of rRNA was followed by a robust G1 arrest, and activation of apoptotic proteins caspase-8, -9, and -3 and PARP-1 in a p53-independent manner. Using cell synchronization and flow cytometry, it was determined that cells treated while in G1 arrest immediately, but cells treated in S or G2 successfully complete mitosis. Twenty-four hours after treatment, the majority of cells finally arrest in G1, but nearly one-third contained highly compacted DNA; a distinct biological feature that cannot be associated with mitosis, senescence, or apoptosis. This unique effect mirrored the efficient condensation of tRNA and DNA in cell-free systems. The combination of DNA compaction and apoptosis by TriplatinNC treatment conferred striking activity in platinum-resistant and/or p53 mutant or null cell lines. Taken together, our results support that the biological activity of TriplatinNC reflects reduced metabolic deactivation (substitution-inert compound not reactive to sulfur nucleophiles), high cellular accumulation, and novel consequences of high-affinity noncovalent DNA binding, producing a new profile and a further shift in the structure–activity paradigms for antitumor complexes.
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DOI：
10.1039/c0cc01254h
发表时间：
2010-09-28
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Mangrum JB;Farrell NP
通讯作者：
Farrell NP
影响因子：
5.6
作者：
Derenzini, M;Montanaro, L;Treré, D
通讯作者：
Treré, D
影响因子：
4.9
作者：
Benedetti BT;Peterson EJ;Kabolizadeh P;Martínez A;Kipping R;Farrell NP
通讯作者：
Farrell NP
影响因子：
5.7
作者：
Benedetti, Valentina;Perego, Paola;Zunino, Franco
通讯作者：
Zunino, Franco
DOI：
10.1016/s0027-5107(03)00005-8
发表时间：
2003-05-15
影响因子：
2.3
作者：
Khynriam, D;Prasad, SB
通讯作者：
Prasad, SB