CORM-3 induces DNA damage through Ru(II) binding to DNA.
CORM-3 induces DNA damage through Ru(II) binding to DNA.
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DOI：
10.1042/bcj20220254
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发表时间：
2022-07-15
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当‘CO释放分子-3’，CORM-3(Ru(CO)3CL(甘氨酸))溶于水中时，它形成一系列的Ru络合物。它们被细胞摄取并与细胞内的配体结合，特别是半胱氨酸和谷胱甘肽等硫醇，其中Ru(II)达到较高的细胞内浓度。在这里，我们表明，Ru(II)离子也与DNA结合，在暴露的鸟苷N7位。因此，它的细胞靶点与抗癌药物顺铂相似，但不完全相同，因为没有证据表明Ru(II)在DNA中形成了分子内的交叉桥。反应缓慢，与过量的Ru形成分子间DNA交叉桥。根据碱性彗星试验的评估，CORM-3加入到人类结直肠癌细胞中会导致DNA链断裂。DNA损伤被含有氨基酸的生长介质所抑制，这些氨基酸与细胞外的Ru结合，阻止其进入细胞。我们的结论是，Ru(II)的细胞毒性与铂不同，这使其成为癌症治疗的一个有前途的开发目标。
When the ‘CO-releasing molecule-3’, CORM-3 (Ru(CO)3Cl(glycinate)), is dissolved in water it forms a range of ruthenium complexes. These are taken up by cells and bind to intracellular ligands, notably thiols such as cysteine and glutathione, where the Ru(II) reaches high intracellular concentrations. Here, we show that the Ru(II) ion also binds to DNA, at exposed guanosine N7 positions. It therefore has a similar cellular target to the anticancer drug cisplatin, but not identical, because Ru(II) shows no evidence of forming intramolecular crossbridges in the DNA. The reaction is slow, and with excess Ru, intermolecular DNA crossbridges are formed. The addition of CORM-3 to human colorectal cancer cells leads to strand breaks in the DNA, as assessed by the alkaline comet assay. DNA damage is inhibited by growth media containing amino acids, which bind to extracellular Ru and prevent its entry into cells. We conclude that the cytotoxicity of Ru(II) is different from that of platinum, making it a promising development target for cancer therapeutics.