错配修复缺陷细胞中铑金属插入剂的选择性细胞毒性。
Selective cytotoxicity of rhodium metalloinsertors in mismatch repair-deficient cells.
机构信息
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
出版信息
Biochemistry. 2011 Dec 20;50(50):10919-28. doi: 10.1021/bi2015822. Epub 2011 Nov 21.
Abstract
Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anticancer agents.
摘要
DNA 中的错配在复制过程中自然发生，并且是内源性 DNA 损伤剂的结果，但是错配修复 (MMR) 途径在随后的复制轮次之前作用于纠正错配。铑金属插入剂与 DNA 错配具有高亲和力和特异性结合，代表了靶向细胞中错配的有前途的策略。在这里，我们研究了在 MMR 缺陷型细胞与 MMR 功能正常的细胞中，带有二吡啶基胺辅助配体的铑金属插入剂的生物学命运。这些复合物显示出加速的细胞摄取，从而允许观察各种细胞反应，包括通过流式细胞术检测到的细胞周期中断，以及通过染料排除和半胱天冬酶抑制测定法监测到的坏死诱导，这些反应优先发生在 MMR 缺陷型细胞系中。这些细胞反应为理解这种新型靶向抗癌剂的选择性活性的机制提供了线索。
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