Cell-selective biological activity of rhodium metalloinsertors correlates with subcellular localization.
Cell-selective biological activity of rhodium metalloinsertors correlates with subcellular localization.
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DOI：
10.1021/ja3090687
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发表时间：
2012-11-21
影响因子：
15
通讯作者：
Barton, Jacqueline K.
中科院分区：
文献类型：
--
作者：
Komor, Alexis C.;Schneider, Curtis J.;Weidmann, Alyson G.;Barton, Jacqueline K.
错配修复（MMR）途径的缺陷与几种类型的癌症以及对常用化疗药物的耐药性有关。铑金属插入物在体外具有高亲和力和特异性结合DNA错配，并且还表现出细胞选择性细胞毒性，靶向mmr缺陷细胞而不是mmr熟练细胞。合成了10种不同的亲脂性金属插入子，并测定了它们的错配结合亲和力和生物活性。虽然DNA光裂解实验表明它们的结合亲和力非常相似，但它们的细胞选择性抗增殖和细胞毒性活性却有很大差异。电感耦合等离子体质谱（ICP-MS）实验揭示了这些金属插入物的亚细胞分布与其生物活性之间的关系。具体来说，我们发现所有的金属插入子都以足够的浓度定位于细胞核中，以结合DNA错配。然而，在线粒体中具有高铑定位的金属插入子对mmr缺陷细胞显示出不选择性的毒性，而具有较少线粒体铑的金属插入子对mmr缺陷细胞显示出高度选择性的活性。这项工作支持了金属插入子特异性靶向核DNA产生细胞选择性细胞毒性和抗增殖活性的观点。细胞靶向的选择性取决于与基因组DNA错配的结合。
Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells. Ten distinct metalloinsertors with varying lipophilicities have been synthesized and their mismatch binding affinities and biological activities determined. Although DNA photocleavage experiments demonstrate that their binding affinities are quite similar, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments have uncovered a relationship between the subcellular distribution of these metalloinsertors and their biological activities. Specifically, we find that all of our metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. However, the metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells, whereas metalloinsertors with less mitochondrial rhodium show activity that is highly selective for MMR-deficient versus proficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cell-selective cytotoxic and antiproliferative activities. The selectivity in cellular targeting depends upon binding to mismatches in genomic DNA.
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DOI：
10.1039/c39870001724
发表时间：
1987-11-15
影响因子：
--
作者：
BASU, A;BHADURI, S;JONES, PG
通讯作者：
JONES, PG
影响因子：
11.2
作者：
Ahmad, KA;Iskandar, KB;Pervaiz, S
通讯作者：
Pervaiz, S
DOI：
10.1073/pnas.0537194100
发表时间：
2003-04-01
影响因子：
11.1
作者：
Junicke, H;Hart, JR;Barton, JK
通讯作者：
Barton, JK
影响因子：
2.9
作者：
Jackson, BA;Barton, JK
通讯作者：
Barton, JK
影响因子：
2.9
作者：
Jackson, BA;Alekseyev, VY;Barton, JK
通讯作者：
Barton, JK