Antiproliferative mechanisms of action of the flavin dehydrogenase inhibitors diphenylene iodonium and di-2-thienyliodonium based on molecular profiling of the NCI-60 human tumor cell panel.
Antiproliferative mechanisms of action of the flavin dehydrogenase inhibitors diphenylene iodonium and di-2-thienyliodonium based on molecular profiling of the NCI-60 human tumor cell panel.
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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。
DOI：
10.1016/j.bcp.2012.01.022
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发表时间：
2012-05-01
影响因子：
5.8
通讯作者：
Roy, Krishnendu
中科院分区：
文献类型：
--
作者：
Doroshow, James H.;Juhasz, Agnes;Ge, Yun;Holbeck, Susan;Lu, Jiamo;Antony, Smitha;Wu, Yongzhong;Jiang, Guojian;Roy, Krishnendu
关键词：
黄蛋白依赖的活性氧（ROS）在正常组织和肿瘤细胞的细胞因子介导的信号转导中起着关键作用。黄酶抑制剂二苯基碘（DPI）和二-2-噻吩碘（DTI）已被用于抑制膜结合的含黄蛋白的NADPH氧化酶，包括上皮和白细胞的NADPH氧化酶（Nox1-5和Duox 1和2）。近期研究表明，DPI可抑制肿瘤细胞增殖；然而，所涉及的分子机制仍然不明确。为了探索DPI-和dti相关肿瘤细胞生长延迟的机制，我们在NCI-60肿瘤组中检测了这两种药物产生的生长抑制模式，并测定了这些细胞系中Nox基因家族成员的表达水平。使用COMPARE程序预测可能的分子靶标。DPI比DTI更有效（GI50: 10 nM vs 10 μM）；当对照国家癌症研究所的小分子抗癌数据库进行评估时，DPI和DTI暴露产生了独特的生长抑制模式。DPI的生长抑制谱显示与Nox1水平适度正相关；通过与NCI-60 Affymetrix®阵列数据的相关性推断DPI和DTI作用的新机制，包括Stat、Erk1/2和Akt通路的改变。将表达Nox1的HT-29结肠癌细胞暴露于DPI和DTI中，证实了它们对稳态ROS水平的抑制作用，并表明IL-4、IL-6、IL-13和IL-22介导的Stat、Erk1/2和Akt信号的降低，可能是由于肿瘤细胞磷酸酶活性的增加。这些发现表明DPI和DTI可能通过改变ros相关的信号转导起到治疗作用。
Flavoprotein-dependent reactive oxygen species (ROS) play a critical role in cytokine-mediated signal transduction in normal tissues and tumor cells. The flavoenzyme inhibitors diphenylene iodonium (DPI) and di-2-thienyliodonium (DTI) have been used to inhibit membrane-bound, flavoprotein-containing NADPH oxidases, including epithelial and leukocyte NADPH oxidases (Nox1-5 and Duox 1 and 2). Recent evidence suggests that DPI can decrease tumor cell proliferation; however, the molecular mechanisms involved remain poorly defined. To explore the mechanisms underlying DPI- and DTI-related tumor cell growth delay, we examined growth inhibition patterns produced by both agents in the NCI-60 tumor panel, and determined expression levels of Nox gene family members across these cell lines. Possible molecular targets were predicted using the COMPARE program. DPI was more potent than DTI (GI50: 10 nM versus 10 μM); DPI and DTI exposure produced unique patterns of growth inhibition when evaluated against the small molecule anticancer database of the National Cancer Institute. Growth inhibition profiling of DPI revealed a modest positive correlation with Nox1 levels; novel mechanisms of DPI and DTI action, including alterations in Stat, Erk1/2, and Akt pathways, were inferred by correlation with NCI-60 Affymetrix® array data. Exposure of HT-29 colon cancer cells, which express Nox1, to DPI and DTI confirmed their inhibitory effects on steady state ROS levels, and demonstrated decreased Stat, Erk1/2, and Akt signaling mediated by IL-4, IL-6, IL-13, and IL-22, possibly due to a concomitant increase in tumor cell phosphatase activity. These findings suggest that DPI and DTI may act therapeutically by altering ROS-related signal transduction.
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影响因子：
5.3
作者：
Coant, Nicolas;Ben Mkaddem, Sanae;Ogier-Denis, Eric
通讯作者：
Ogier-Denis, Eric
影响因子：
4.8
作者：
Block, Karen;Gorin, Yves;Abboud, Hanna E.
通讯作者：
Abboud, Hanna E.
NADPH 氧化酶同源物和辅助基因在人类癌细胞系、肿瘤和邻近正常组织中的表达。
影响因子：
3.3
作者：
Juhasz A;Ge Y;Markel S;Chiu A;Matsumoto L;van Balgooy J;Roy K;Doroshow JH
通讯作者：
Doroshow JH
影响因子：
4.1
作者：
GATLEY, SJ;SHERRATT, HSA
通讯作者：
SHERRATT, HSA
影响因子：
4.8
作者：
Hutchinson, Dana S.;Csikasz, Robert I.;Bengtsson, Tore
通讯作者：
Bengtsson, Tore