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首页> 外文期刊>Marine Drugs >Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase IIα Activity Through ATP-Competitive Inhibition
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Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase IIα Activity Through ATP-Competitive Inhibition

机译：新安非他明通过ATP竞争性抑制作用来消除羟甲基酶增强的DNA拓扑异构酶IIα活性。

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Type IIα DNA topoisomerase (TopoIIα) is among the most important clinical drug targets for the treatment of cancer. Recently, the DNA repair protein Metnase was shown to enhance TopoIIα activity and increase resistance to TopoIIα poisons. Using in vitro DNA decatenation assays we show that neoamphimedine potently inhibits TopoIIα-dependent DNA decatenation in the presence of Metnase. Cell proliferation assays demonstrate that neoamphimedine can inhibit Metnase-enhanced cell growth with an IC50 of 0.5 μM. Additionally, we find that the apparent Km of TopoIIα for ATP increases linearly with higher concentrations of neoamphimedine, indicating ATP-competitive inhibition, which is substantiated by molecular modeling. These findings support the continued development of neoamphimedine as an anticancer agent, particularly in solid tumors that over-express Metnase.
机译：IIα型DNA拓扑异构酶（TopoIIα）是治疗癌症最重要的临床药物靶标之一。最近，DNA修复蛋白Metnase被证明可以增强TopoIIα活性并增强对TopoIIα毒物的抵抗力。使用体外DNA脱脂测定法，我们显示在存在Metnase的情况下，新安非他命可有效抑制TopoIIα依赖性DNA脱脂。细胞增殖试验表明，新安非他明可以抑制Metnase增强的细胞生长，IC 50 为0.5μM。此外，我们发现，TopoIIα对于ATP的表观K m 随着新安非他明浓度的升高而线性增加，这表明ATP竞争性抑制作用已通过分子模拟得到证实。这些发现支持了新安非他明作为抗癌剂的持续发展，特别是在过表达Metnase的实体肿瘤中。

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