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首页> 外文期刊>Molecular cancer therapeutics >Subcellular distribution of a fluorescence-labeled combi-molecule designed to block epidermal growth factor receptor tyrosine kinase and damage DNA with a green fluorescent species.
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Subcellular distribution of a fluorescence-labeled combi-molecule designed to block epidermal growth factor receptor tyrosine kinase and damage DNA with a green fluorescent species.

机译：荧光标记的组合分子的亚细胞分布，该组合分子旨在阻止表皮生长因子受体酪氨酸激酶并以绿色荧光物质破坏DNA。

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摘要

To monitor the subcellular distribution of mixed epidermal growth factor (EGF) receptor (EGFR)-DNA targeting drugs termed combi-molecules, we designed AL237, a fluorescent prototype, to degrade into a green fluorescent DNA damaging species and FD105, a blue fluorescent EGFR inhibitor. Here we showed that AL237 damaged DNA in the 12.5 to 50 mumol/L range. Despite its size, it blocked EGFR phosphorylation in an enzyme assay (IC(50) = 0.27 mumol/L) and in MDA-MB468 breast cancer cells in the same concentration range as for DNA damage. This translated into inhibition of extracellular signal-regulated kinase 1/2 or BAD phosphorylation and downregulation of DNA repair proteins (XRCC1, ERCC1). Having shown that AL237 was a balanced EGFR-DNA targeting molecule, it was used as an imaging probe to show that (a) green and blue colors were primarily colocalized in the perinuclear and partially in the nucleus in EGFR- or ErbB2-expressing cells, (b) the blue fluorescence associated with FD105, but not the green, was colocalized with anti-EGFR red-labeled antibody, (c) the green fluorescence of nuclei was significantly more intense in NIH 3T3 cells expressing EGFR or ErbB2 than in their wild-type counterparts (P < 0.05). Similarly, the growth inhibitory potency of AL237 was selectively stronger in the transfectants. In summary, the results suggest that AL237 diffuses into the cells and localizes abundantly in the perinuclear region and partially in the nucleus where it degrades into EGFR and DNA targeting species. This bystander-like effect translates into high levels of DNA damage in the nucleus. Sufficient quinazoline levels are released in the cells to block EGF-induced activation of downstream signaling. Mol Cancer Ther; 9(4); 869-82. (c)2010 AACR.
机译：为监测混合表皮生长因子（EGF）受体（EGFR）-DNA靶向组合药物的亚细胞分布，我们设计了AL237（一种荧光原型）降解为绿色荧光DNA破坏物种，而FD105则降解为蓝色荧光EGFR。抑制剂。在这里，我们表明AL237可以破坏12.5至50μmol/ L范围内的DNA。尽管它的大小，它在酶测定（IC（50）= 0.27 mumol / L）和MDA-MB468乳腺癌细胞中以与DNA损伤相同的浓度范围阻止了EGFR磷酸化。这转化为抑制细胞外信号调节激酶1/2或BAD磷酸化，并下调DNA修复蛋白（XRCC1，ERCC1）。已经表明AL237是一种平衡的EGFR-DNA靶向分子，它被用作成像探针以显示（a）绿色和蓝色主要共存在于表达EGFR或ErbB2的细胞的核周中，部分在核中， （b）与FD105相关的蓝色荧光与未与FD105相关的绿色荧光与抗EGFR红色标记的抗体共定位，（c）在表达EGFR或ErbB2的NIH 3T3细胞中，其核的绿色荧光明显比在野生环境中强型对应物（P <0.05）。类似地，在转染子中AL237的生长抑制能力选择性增强。总之，结果表明AL237扩散到细胞中，并大量分布在核周区域和部分细胞核中，在那里它降解为EGFR和DNA靶向物种。这种类似旁观者的效应转化为细胞核中高水平的DNA损伤。足够的喹唑啉水平在细胞中释放，以阻断EGF诱导的下游信号传导激活。分子癌疗法; 9（4）; 869-82。 （c）2010年美国机管学会（AACR）。

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