缺氧靶向药物 Q6 通过在缺氧条件下毒害拓扑异构酶 II 诱导 G2-M 期阻滞和凋亡。
Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia.
机构信息
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
出版信息
PLoS One. 2015 Dec 9;10(12):e0144506. doi: 10.1371/journal.pone.0144506. eCollection 2015.
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.
尽管人们为开发缺氧激活前药付出了巨大努力，但目前尚无药物被批准用于临床治疗。在本研究中，我们研究了一种新型替拉扎胺（TPZ）类似物 7-甲基-3-（3-氯苯基）-喹喔啉-2-甲腈 1,4-二氧化物（Q6）的缺氧选择性抗癌活性及其细胞靶标。Q6 在缺氧条件下通过抑制拓扑异构酶 II（topo II）发挥抗癌作用。改良的琼脂糖 DNA 免疫染色（TARDIS）检测表明，即使在更低的浓度下，Q6 比 TPZ 捕获更多的拓扑异构酶 II-DNA 断裂复合物。此外，通过引入共济失调毛细血管扩张突变（ATM）激酶抑制剂咖啡因和 KU-60019，我们发现 Q6 诱导的细胞凋亡至少部分归因于由拓扑异构酶 II 靶向作用产生的 DNA 双链断裂。总之，与母体化合物 TPZ 相比，Q6 具有更好的缺氧选择性和拓扑异构酶 II 抑制作用。所有这些数据为 Q6 作为一种有前途的缺氧激活前药候选物用于人类肝细胞癌治疗的研究提供了依据。
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