Activation of aminoflavone (NSC 686288) by a sulfotransferase is required for the antiproliferative effect of the drug and for induction of histone γ-H2AX
Activation of aminoflavone (NSC 686288) by a sulfotransferase is required for the antiproliferative effect of the drug and for induction of histone γ-H2AX
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DOI：
10.1158/0008-5472.can-06-0796
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Meng, Ling-hua;Shankavaram, Uma;Pommier, Yves
氨基曲酮（AF）正在进入临床试验阶段。我们最近报道了AF在MCF-7人乳腺癌细胞中诱导dna -蛋白交联（DPC）和γ - h2ax。为了阐明AF的作用机制并提供指示AF活性的生物标志物，我们将AF活性谱（GI(50)）与NCI-60细胞系的基因表达模式相关联。硫转移酶（SULT）的正相关系数最高（r = 0.537, P < 0.001）。将SULT1A1稳定转染到抗AF的MDA-MB-231细胞中，使这些细胞对AF敏感。在SULT1A1转染的MDA-MB-231细胞中，AF产生DPCs、γ - h2ax灶和s期阻滞，而在母体MDA-MB-231细胞中则没有。相反，SULT1A1被小干扰RNA敲低的细胞不能诱导γ - h2ay -天然黄酮类化合物抑制SULTs和细胞色素P450 （CYP）酶可阻断AF的抗增殖活性和AF- dna加合物的形成。AF还能诱导MCF-7细胞中SULT1A1和CYP的表达，提示存在芳烃受体介导的CYP和SULT1A1激活AF的正反馈。代谢研究表明，AF可以被CYP在两个氨基上氧化形成n -羟基代谢物，这些代谢物是SULTs生物激活的底物。我们提出，这两个n -亚砜基可以进一步转化为与DNA和蛋白质形成加合物的氮离子。本文报道的结果显示了SULT1A1和CYP对AF激活和抗癌活性的重要性。他们还建议在患者选择和临床试验监测期间使用SULT1A1和γ - h2ax作为AF活动预测的生物标志物。
Aminotlavone (AF) is entering clinical trials. We recently reported that AF induces DNA-protein cross-links (DPC) and gamma-H2AX in MCF-7 human breast cancer cells. To elucidate the mechanism of action of AF and provide biomarkers indicative of AF activity, we correlated AF activity profile (GI(50)) with gene expression patterns in the NCI-60 cell lines. Sulfotransferases (SULT) showed the highest positive correlation coefficients among similar to 14,000 probe sets analyzed (r = 0.537, P < 0.001). Stable transfection of SULT1A1 into AF-resistant MDA-MB-231 cells sensitized these cells to AF. AF produced DPCs, gamma-H2AX foci, and S-phase arrest in the SULT1A1-transfected but not in the parent MDA-MB-231 cells. Conversely, cells in which SULT1A1 was knocked down by small interfering RNA failed to induce gamma-H2AY- Inhibition of SULTs and cytochrome P450 (CYP) enzymes by natural flavonoids blocked the antiproliferative activity of AF and the formation of AF-DNA adducts. AF also induces SULT1A1 and CYP expression in MCF-7 cells, suggesting the existence of an aryl hydrocarbon receptor-mediated positive feedback for AF activation by CYP and SULT1A1. Metabolism studies showed that AF can be oxidized by CYP at two amino groups to form N-hydroxyl metabolites that are substrates for bioactivation by SULTs. We propose that both N-sulfoxy-groups can be further converted to nitrenium ions that form adducts with DNA and proteins. The results reported here show the importance of SULT1A1 and CYP for AF activation and anticancer activity. They also suggest using SULT1A1 and gamma-H2AX as biomarkers for prediction of AF activity during patient selection and monitoring of clinical trials.