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首页> 美国卫生研究院文献>Antioxidants >Cancer Cell Sensitivity to Redox-Cycling Quinones is Influenced by NAD(P)H: Quinone Oxidoreductase 1 Polymorphism
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Cancer Cell Sensitivity to Redox-Cycling Quinones is Influenced by NAD(P)H: Quinone Oxidoreductase 1 Polymorphism

机译：癌细胞对氧化还原循环醌的敏感性受NAD（P）H：醌氧化还原酶1多态性的影响。

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Background: Cancer cell sensitivity to drugs may be associated with disturbed antioxidant enzymes expression. We investigated mechanisms of resistance by using oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). Since nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase-1 (NQO1) is modified in tumors and oxidative stress-resistant cells, we studied its role in cells exposed to β-lapachone, menadione, and doxorubicin. Methods: Normal mammary epithelial 250MK, MCF-7, and Resox cells were employed. NQO1 expression and enzyme activity were determined by quantitative polymerase chain reaction (RT-PCR), immunoblotting, and biochemical assays. Dicoumarol and gene silencing (siRNA) were used to modulate NQO1 expression and to assess its potential drug-detoxifying role. MTT (3-(4,5-dimethylthia-zolyl-2)-2,5-diphenyltetrazolium bromide) or clonogenic assays were used to investigate cytotoxicity. NQO1 variants, NQO1*1 (wt), and NQO1*2 (C609T), were obtained by transfecting NQO1-null MDA-MB-231 cell line. Results: Resox cells have higher NQO1 expression than MCF-7 cells. In 250MK cells its expression was low but enzyme activity was higher suggesting a variant NQO1 form in MCF-7 cells. MCF-7 and Resox cells are heterozygous NQO1*1 (wt)/NQO1*2 (C609T). Both NQO1 polymorphism and NQO1 overexpression are main determinants for cell resistance during oxidative stress. NQO1 overexpression increases cell sensitivity to β-lapachone whereas NQO1*2 polymorphism triggers quinone-based chemotherapies-sensitivity. Conclusions: NQO1 influences cancer cells redox metabolism and their sensitivity to drugs. We suggest that determining NQO1 polymorphism may be important when considering the use of quinone-based chemotherapeutic drugs.
机译：背景：癌细胞对药物的敏感性可能与抗氧化酶表达紊乱有关。我们通过使用抗氧化应激的MCF-7乳腺癌细胞（Resox细胞）研究了耐药机制。由于烟酰胺腺嘌呤二核苷酸磷酸（NAD（P）H）：醌氧化还原酶-1（NQO1）在肿瘤和氧化应激抗性细胞中被修饰，因此我们研究了其在暴露于β-拉帕酮，甲萘醌和阿霉素的细胞中的作用。方法：采用正常的乳腺上皮细胞250MK，MCF-7和Resox细胞。 NQO1表达和酶活性通过定量聚合酶链反应（RT-PCR），免疫印迹和生化测定来确定。使用双香豆酚和基因沉默（siRNA）来调节NQO1的表达并评估其潜在的排毒作用。使用MTT（3-（4,5-二甲基噻唑-唑基-2）-2,5-二苯基四唑鎓溴化物）或克隆形成试验来研究细胞毒性。 NQO1变体NQO1 * 1（wt）和NQO1 * 2（C609T）通过转染NQO1-null MDA-MB-231细胞系获得。结果：Resox细胞比MCF-7细胞具有更高的NQO1表达。在250MK细胞中，其表达较低，但酶活性较高，表明MCF-7细胞中存在NQO1变体形式。 MCF-7和Resox细胞是杂合的NQO1 * 1（wt）/ NQO1 * 2（C609T）。 NQO1多态性和NQO1过表达均是氧化应激期间细胞抗性的主要决定因素。 NQO1过表达增加了细胞对β-lapachone的敏感性，而NQO1 * 2多态性则触发了基于醌的化学敏感性。结论：NQO1影响癌细胞的氧化还原代谢及其对药物的敏感性。我们建议，在考虑使用基于醌的化学治疗药物时，确定NQO1多态性可能很重要。

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