Upregulation of NAD(P)H: quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells
Upregulation of NAD(P)H: quinone oxidoreductase by radiation potentiates the effect of bioreductive β-lapachone on cancer cells
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DOI：
10.1593/neo.07397
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发表时间：
2007-08-01
期刊：
影响因子：
4.8
通讯作者：
Park, Heon Joo
中科院分区：
文献类型：
--
作者：
Choi, Eun K.;Terai, Kaoru;Park, Heon Joo
我们发现一种新型生物还原药物B-lapachone （β -lap）在体外诱导A549人肺上皮细胞快速凋亡和克隆源性细胞死亡，并呈剂量依赖性。NAD(P) H：醌氧化还原酶（NQO1）抑制剂双oumarol和NQO1 siRNA均能显著抑制β -lap诱导的克隆性细胞死亡，说明NQO1诱导的β -lap生物还原是β -lap诱导的细胞死亡的必要步骤。4gy辐照A549细胞引起NQO1的持续上调，从而增加NQO1介导的β -lap诱导的细胞死亡。虽然β -lap诱导细胞凋亡的直接原因尚不清楚，但β -lap处理降低了p53和NF-kappa B的表达，而增加了细胞色素C的释放、caspase-3活性和；H2AX聚焦形成。重要的是，在辐照后立即进行β -lap治疗增强了辐射诱导的细胞死亡，这表明β -lap除了直接杀死一些细胞外，还使癌细胞对辐射敏感。在免疫功能低下小鼠中，局部放射治疗后再加β -lap治疗可明显抑制A549肿瘤的生长。这是第一个证明联合放疗和β -lap治疗对人类肿瘤异种移植有显著影响的研究。
We found that B-lapachone (beta-lap), a novel bioreductive drug, caused rapid apoptosis and clonogenic cell death in A549 human lung epithelial cancer cells in vitro in a dose-dependent manner. The clonogenic cell death caused by beta-lap could be significantly inhibited by dicoumarol, an inhibitor of NAD( P) H: quinone oxidoreductase (NQO1), and also by siRNA for NQO1, demonstrating that NQO1-induced bioreduction of beta-lap is an essential step in beta-lap-induced cell death. Irradiation of A549 cells with 4 Gy caused a long-lasting upregulation of NQO1, thereby increasing NQO1-mediated beta-lap-induced cell deaths. Although the direct cause of beta-lap-induced apoptosis is not yet clear, beta-lap treatment reduced the expression of p53 and NF-kappa B, whereas it increased cytochrome C release, caspase-3 activity, and; gamma H2AX foci formation. Importantly, beta-lap treatment immediately after irradiation enhanced radiation-induced cell death, indicating that beta-lap sensitizes cancer cells to radiation, in addition to directly killing some of the cells. The growth of A549 tumors induced in immunocompromised mice could be markedly suppressed by local radiation therapy when followed by beta-lap treatment. This is the first study to demonstrate that combined radiotherapy and beta-lap treatment can have a significant effect on human tumor xenografts.