Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia
Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia
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缺氧靶向药物 Q6 在缺氧下通过中毒拓扑异构酶 II 诱导 G2-M 期阻滞和细胞凋亡
DOI：
10.1371/journal.pone.0144506
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发表时间：
2015-12-09
期刊：
影响因子：
3.7
通讯作者：
Zhu, Hong
中科院分区：
文献类型：
--
作者：
Chang, Linlin;Liu, Xiaowen;Zhu, Hong
尽管在开发缺氧激活前药方面做出了巨大的努力，但尚未有药物被批准用于临床治疗。在本研究中，研究了一种新型替拉帕嗪（TPZ）类似物7-甲基-3-（3-氯苯基）-喹啉-2-碳腈1,4-二氧化酯（Q6）的缺氧选择性抗癌活性及其细胞靶点。Q6在缺氧条件下通过中毒拓扑异构酶II （topo II）发挥抗癌作用。在琼脂糖DNA免疫染色（TARDIS）实验中，Q6比TPZ在更低浓度下捕获了更多的拓扑II-DNA切割复合物。此外，通过引入ataxa -毛细血管扩张突变（ATM）激酶抑制剂咖啡因和KU-60019，我们发现q6触发的细胞凋亡至少部分归因于topo ii靶向效应产生的DNA双链断裂。总的来说，Q6比亲本化合物TPZ具有更好的缺氧选择性和拓扑ii中毒。所有这些数据为Q6作为一种有前景的缺氧激活前药候选药物治疗人肝癌提供了线索。
In spite of the tremendous efforts dedicated to developing hypoxia-activated prodrugs, no agents yet have been approved for clinical therapy. In the present study, the hypoxic selective anti-cancer activity as well as the cellular target of a novel tirapazamine (TPZ) analogue, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (Q6) were investigated. Q6 implemented anti-cancer effects via poisoning topoisomerase II (topo II) under hypoxia. Modified trapped in agarose DNA immunostaining (TARDIS) assay showed more topo II–DNA cleavage complexes trapped by Q6 than TPZ at even lower concentration. In addition, by introducing ataxia-telangiectasia-mutated (ATM) kinase inhibitors caffeine and KU-60019, we displayed that Q6-triggered apoptosis was attributed, at least partially, to DNA double-strand breaks generated by the topo II-targeting effect. Collectively, Q6 stood out for its better hypoxia-selectivity and topo II-poisoning than the parental compound TPZ. All these data shed light on the research of Q6 as a promising hypoxia-activated prodrug candidate for human hepatocellular carcinoma therapy.