Ru binding to RNA following treatment with the antimetastatic prodrug NAMI-A in Saccharomyces cerevisiae and in vitro.
Ru binding to RNA following treatment with the antimetastatic prodrug NAMI-A in Saccharomyces cerevisiae and in vitro.
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DOI：
10.1007/s00775-011-0806-7
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发表时间：
2011-12
影响因子：
3
通讯作者：
Holman, Karen L. McFarlane
中科院分区：
文献类型：
--
作者：
Hostetter, Alethia A.;Miranda, Michelle L.;DeRose, Victoria J.;Holman, Karen L. McFarlane
[ImH][trans-RuIIICl 4（DMSO）（Im）]（其中DMSO是二甲基亚砜，Im是咪唑）（NAMI-A）是目前处于II期临床试验的抗转移前药。这种抗癌剂和相关的钌基抗癌剂的作用机制尚不清楚，但已提出了几个细胞靶点。尽管Ru在体外NAMI-A暴露后被观察到与DNA结合，但对体内Ru-DNA相互作用知之甚少，甚至更少了解这种或相关金属药物如何影响细胞RNA。在这项研究中，钌积累在细胞RNA的测定酿酒酵母与NAMI-A处理后。药物依赖性生长和细胞活力表明相对较高的耐受性，450 µM NAMI-A在6 h时发生约40%的细胞死亡。显着的剂量依赖性积累钌细胞RNA中观察到电感耦合等离子体质谱测量RNA提取酵母处理NAMI-A。在体外，结合钌物种的药物处理的模型DNA和RNA寡核苷酸在pH 6.0和7.4的特征在于基质辅助激光解吸/电离飞行时间质谱的存在和不存在的还原剂抗坏血酸。Ru-核苷酸相互作用的程度略有增加，较低的pH值和显着的抗坏血酸的存在下，观察到的物种分布的差异。总之，这些研究表明NAMI-A的水合和还原衍生物在体外和细胞中在RNA上的积累，以及在肿瘤样酸性还原环境中与核酸靶标的结合增强。据我们所知，这也是第一个研究，以表征NAMI-A治疗S。cerevisiae，一种遗传学上易处理的模式生物。
[ImH][trans-RuIIICl4(DMSO)(Im)] (where DMSO is dimethyl sulfoxide and Im is imidazole) (NAMI-A) is an antimetastatic prodrug currently in phase II clinical trials. The mechanisms of action of this and related Ru-based anticancer agents are not well understood, but several cellular targets have been suggested. Although Ru has been observed to bind to DNA following in vitro NAMI-A exposure, little is known about Ru–DNA interactions in vivo and even less is known about how this or related metallodrugs might influence cellular RNA. In this study, Ru accumulation in cellular RNA was measured following treatment of Saccharomyces cerevisiae with NAMI-A. Drug-dependent growth and cell viability indicate relatively high tolerance, with approximately 40% cell death occurring at 6 h for 450 µM NAMI-A. Significant dose-dependent accumulation of Ru in cellular RNA was observed by inductively coupled plasma mass spectrometry measurements on RNA extracted from yeast treated with NAMI-A. In vitro, binding of Ru species to drug-treated model DNA and RNA oligonucleotides at pH 6.0 and 7.4 was characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in the presence and absence of the reductant ascorbate. The extent of Ru–nucleotide interactions increases slightly with lower pH and significantly in the presence of ascorbate, with differences in observed species distribution. Taken together, these studies demonstrate the accumulation of aquated and reduced derivatives of NAMI-A on RNA in vitro and in cellulo, and enhanced binding with nucleic acid targets in a tumorlike acidic, reducing environment. To our knowledge, this is also the first study to characterize NAMI-A treatment of S. cerevisiae, a genetically tractable model organism.
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DOI：
10.1016/j.biocel.2009.08.007
发表时间：
2009-12-01
影响因子：
4
作者：
Jetzt, Amanda E.;Cheng, Ju-Shun;Cohick, Wendie S.
通讯作者：
Cohick, Wendie S.
DOI：
10.1111/j.1349-7006.1992.tb01959.x
发表时间：
1992-05
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Akaboshi M;Kawai K;Maki H;Akuta K;Ujeno Y;Miyahara T
通讯作者：
Miyahara T
影响因子：
3
作者：
Brindell, Malgorzata;Stawoska, Iwona;van Eldik, Rudi
通讯作者：
van Eldik, Rudi
影响因子：
3.4
作者：
Bergamo, A;Messori, L;Sava, G
通讯作者：
Sava, G
影响因子：
3.9
作者：
Heminger, KA;Hartson, SD;Matts, RL
通讯作者：
Matts, RL