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首页> 外文期刊>Biochemical Pharmacology >Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated.
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Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated.

机译：DNA依赖性蛋白激酶和共济失调毛细血管扩张的小分子抑制剂使乳腺癌细胞对电离辐射敏感。

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摘要

DNA-PK and ATM are members of the phosphatidylinositol 3'-kinase like kinase (PIKK) family of serine/threonine protein kinases and have critical roles in the cellular response to DNA double-strand breaks. Genetic loss of either activity leads to pronounced sensitivity to ionizing radiation (IR). Hence, these enzymes are potential targets to confer enhanced radiosensitivity on tumour cells. We show that novel inhibitors of either DNA-PK or ATM sensitize breast carcinoma cells to IR. Radiosensitization was accompanied by an apparent DNA repair deficit as measured by the persistence of IR-induced foci of phosphorylated histone H2AX (gammaH2AX foci). These specific inhibitors also allowed us to probe the biochemistry and kinetics of histone H2AX phosphorylation following gamma-irradiation in breast cancer cells with the aim of validating H2AX as a biomarker for DNA-PK or ATM inhibition in vivo. ATM inhibition reduced the initial average intensity of gammaH2AX foci while inhibition of DNA-PK had only a small effect on the initial phosphorylation of H2AX. However, simultaneous treatment with both compounds dramatically reduced gammaH2AX focus intensity, consistent with the reported role of ATM and DNA-PK in IR induced phosphorylation of H2AX.
机译：DNA-PK和ATM是丝氨酸/苏氨酸蛋白激酶的磷脂酰肌醇3'激酶样激酶（PIKK）家族的成员，在细胞对DNA双链断裂的反应中具有关键作用。任一种活性的遗传损失都会导致对电离辐射（IR）的明显敏感性。因此，这些酶是赋予肿瘤细胞增强放射敏感性的潜在靶标。我们表明，DNA-PK或ATM的新型抑制剂可使乳腺癌细胞对IR敏感。放射增敏伴随着明显的DNA修复缺陷，这是通过IR诱导的磷酸化组蛋白H2AX病灶（gammaH2AX病灶）的持续存在来衡量的。这些特异性抑制剂还使我们能够探测乳腺癌细胞中γ射线照射后组蛋白H2AX磷酸化的生物化学和动力学，目的是验证H2AX作为体内DNA-PK或ATM抑制的生物标记。 ATM抑制降低了gammaH2AX焦点的初始平均强度，而DNA-PK的抑制对H2AX的初始磷酸化的影响很小。但是，同时使用这两种化合物进行处理会显着降低gammaH2AX的聚焦强度，这与报道的ATM和DNA-PK在IR诱导的H2AX磷酸化中的作用一致。

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