A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator.
A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator.
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DOI：
10.1039/c7sc03712k
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发表时间：
2018-01-28
期刊：
影响因子：
8.4
通讯作者：
Vallis KA
中科院分区：
文献类型：
--
作者：
Gill MR;Jarman PJ;Halder S;Walker MG;Saeed HK;Thomas JA;Smythe C;Ramadan K;Vallis KA
[Ru(phen)2(tpphz)]2+在食管癌细胞中同时抑制DNA复制，阻断有丝分裂并增强DNA损伤电离辐射。取代惰性钌（ii）多吡啶配合物已被开发为DNA嵌入剂，但细胞DNA损伤反应的这种结合方式在很大程度上尚未被探索。在这里，我们展示了核靶向复合物[Ru(phen)2(tpphz)]2+ （phen = 1,10-菲罗啉，tpphz =四吡啶苯那嗪）在p53缺失的人类食管癌细胞中产生快速而明显的复制叉进展停滞。在这种情况下，复制应激和双链断裂（DSB） DNA损伤反应（DDR）途径被激活，细胞增殖被抑制。此外，有丝分裂进程受到[Ru(phen)2(tpphz)]2+的影响，其中中期染色体纺锤体附着失败的产生导致纺锤体组装检查点（SAC）激活。这种双重作用机制导致有丝分裂指数升高的快速增殖食管癌细胞优先生长抑制。除了这些单药作用外，[Ru(phen)2(tpphz)]2+作为放射增敏剂，其效率与顺铂相当，通过协同增强DNA损伤而发生。这些结果证实了DNA复制是[Ru(phen)2(tpphz)]2+的靶标，并提供了第一个实验证据，表明基于钌的嵌入物靶向癌细胞中的多个基因组完整性途径，从而与现有的DNA损伤剂（如顺铂）相比，实现了更高的选择性。
[Ru(phen)2(tpphz)]2+ simultaneously inhibits DNA replication, blocks mitosis and enhances DNA-damaging ionising radiation in oesophageal cancer cells. Substitutionally inert ruthenium(ii) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen)2(tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53-deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest. Moreover, mitotic progression is compromised by [Ru(phen)2(tpphz)]2+, where the generation of metaphase chromosome spindle attachment failure results in spindle assembly checkpoint (SAC) activation. This dual mechanism of action results in preferential growth inhibition of rapidly-proliferating oesophageal cancer cells with elevated mitotic indices. In addition to these single-agent effects, [Ru(phen)2(tpphz)]2+ functions as a radiosensitizer with efficiency comparable to cisplatin, which occurs through a synergistic enhancement of DNA damage. These results establish that DNA replication is the target for [Ru(phen)2(tpphz)]2+ and provide the first experimental evidence that ruthenium-based intercalation targets multiple genome integrity pathways in cancer cells, thereby achieving enhanced selectivity compared to existing DNA-damaging agents such as cisplatin.
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影响因子：
4
作者：
Campisi, Judith
通讯作者：
Campisi, Judith
影响因子：
8.4
作者：
Griffith C;Dayoub AS;Jaranatne T;Alatrash N;Mohamedi A;Abayan K;Breitbach ZS;Armstrong DW;MacDonnell FM
通讯作者：
MacDonnell FM
诱导癌细胞线粒体介导的细胞凋亡的钌聚吡啶复合物
影响因子：
4.6
作者：
Chen, Tianfeng;Liu, Yanan;Wong, Yum-Shing
通讯作者：
Wong, Yum-Shing
影响因子：
3.5
作者：
Lawrence, TS;Blackstock, AW;McGinn, C
通讯作者：
McGinn, C
影响因子：
11.2
作者：
Koh, Siang-Boon;Courtin, Aurelie;Jodrell, Duncan I.
通讯作者：
Jodrell, Duncan I.