Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts.
Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts.
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碘苯立级黄素脱氢酶抑制剂对生长，活性氧的产生，细胞周期进展，NADPH氧化酶1水平以及人类结肠癌细胞和异种移植物中的基因表达的影响。
DOI：
10.1016/j.freeradbiomed.2013.01.002
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发表时间：
2013-04
影响因子：
7.4
通讯作者：
Juhasz, Agnes
中科院分区：
文献类型：
--
作者：
Doroshow, James H.;Gaur, Shikha;Markel, Susan;Lu, Jiamo;van Balgooy, Josephus;Synold, Timothy W.;Xi, Bixin;Wu, Xiwei;Juhasz, Agnes
碘类黄素蛋白脱氢酶抑制剂已被证明具有抗增殖潜力并抑制人肿瘤细胞中活性氧的产生，尽管解释细胞生长改变与活性氧（ROS）产生之间关系的机制仍然是一个积极研究的领域。由于这些化合物能够抑制含黄素蛋白的上皮NADPH氧化酶的活性，我们选择研究几种碘鎓类黄素蛋白抑制剂对表达高功能水平的单一此类氧化酶（NADPH氧化酶1 [Nox 1]）的人结肠癌细胞系的影响。我们发现，二苯碘鎓（DPI）、二-2-噻吩碘鎓（DTI）和二苯基碘鎓在一定浓度下抑制Caco 2、HT-29和LS-174 T结肠癌细胞的生长。（DPI为10-250 nM，DTI为0.5-2.5 μM，和155 nM至10 μM的碘鎓联苯），显著低于不具有功能性NADPH氧化酶活性的DU 145人前列腺癌细胞。药物治疗与减少过氧化氢的生产和减少细胞内的活性氧水平，持续长达24小时，短期（1小时）暴露于碘类似物。肿瘤细胞增殖的减少部分是由于暴露于DPI或DTI的LS-174 T和HT-29细胞中G1/S界面的细胞周期进展的深度阻滞引起的; LS-174 T细胞的G1期阻滞是通过p27的上调和细胞周期蛋白D1，A，外源H_2O_2可部分抑制E的表达。DPI和DTI不仅降低了细胞内ROS，还显著降低了Nox 1的mRNA表达水平，可能有助于肿瘤细胞活性氧水平的长期降低。我们还发现，DPI和DTI显著降低HT-29和LS-174 T人肿瘤异种移植物的生长，其剂量水平产生的血浆峰浓度与我们体外实验中使用的浓度相似。这些发现表明，碘类似物对体内含有NADPH氧化酶的人类结肠癌具有治疗潜力，并且至少部分的抑制作用机制可能与靶向Nox 1有关。
Iodonium-class flavoprotein dehydrogenase inhibitors have been demonstrated to possess antiproliferative potential and to inhibit reactive oxygen production in human tumor cells, although the mechanism(s) that explain the relationship between altered cell growth and the generation of reactive oxygen species (ROS) remain an area of active investigation. Because of the ability of these compounds to inhibit the activity of flavoprotein-containing epithelial NADPH oxidases, we chose to examine the effects of several iodonium-class flavoprotein inhibitors on human colon cancer cell lines that express high, functional levels of a single such oxidase (NADPH oxidase 1 [Nox1]). We found that diphenylene iodonium (DPI), di-2-thienyliodonium (DTI), and iodoniumdiphenyl inhibited the growth of Caco2, HT-29, and LS-174T colon cancer cells at concentrations (10–250 nM for DPI, 0.5–2.5 μM for DTI, and 155 nM to 10 μM for iodoniumdiphenyl) substantially lower than for DU145 human prostate cancer cells that do not possess functional NADPH oxidase activity. Drug treatment was associated with decreased H2O2 production and diminished intracellular ROS levels, lasting up to 24 hr, following short-term (1-hr) exposure to the iodonium analogs. Decreased tumor cell proliferation was caused, in part, by a profound block in cell cycle progression at the G1/S interface in both LS-174T and HT-29 cells exposed to either DPI or DTI; and the G1 block was produced, for LS-174T cells, by upregulation of p27 and a drug concentration-related decrease in the expression of cyclins D1, A, and E that was partially prevented by exogenous H2O2. Not only did DPI and DTI decrease intracellular ROS, they both also significantly decreased the mRNA expression levels of Nox1, potentially contributing to the prolonged reduction in tumor cell reactive oxygen levels. We also found that DPI and DTI significantly decreased the growth of both HT-29 and LS-174T human tumor xenografts, at dose levels that produced peak plasma concentrations similar to those utilized for our in vitro experiments. These findings suggest that iodonium analogs have therapeutic potential for NADPH oxidase-containing human colon cancers in vivo, and that at least part of their antineoplastic mechanism of action may be related to targeting Nox1.
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基于NCI-60人类肿瘤细胞板的分子谱，黄素脱氢酶抑制剂二苯基二苯和DI-2-噻二乙烯二元的作用机理。
影响因子：
5.8
作者：
Doroshow, James H.;Juhasz, Agnes;Ge, Yun;Holbeck, Susan;Lu, Jiamo;Antony, Smitha;Wu, Yongzhong;Jiang, Guojian;Roy, Krishnendu
通讯作者：
Roy, Krishnendu
影响因子：
8
作者：
Bonner, Michael Y.;Arbiser, Jack L.
通讯作者：
Arbiser, Jack L.
影响因子：
4.8
作者：
Block, Karen;Gorin, Yves;Abboud, Hanna E.
通讯作者：
Abboud, Hanna E.
DOI：
10.1111/j.1432-1033.1992.tb17159.x
发表时间：
1992-08-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
DOUSSIERE, J;VIGNAIS, PV
通讯作者：
VIGNAIS, PV
影响因子：
3.3
作者：
Gianni, Davide;Bohl, Ben;Bokoch, Gary M.
通讯作者：
Bokoch, Gary M.