A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells.
A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells.
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DOI：
10.1021/cb100219n
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发表时间：
2010-10-15
影响因子：
4
通讯作者：
Rosen, Hugh
中科院分区：
文献类型：
--
作者：
Gianni, Davide;Taulet, Nicolas;Zhang, Hui;DerMardirossian, Celine;Kister, Jeremy;Martinez, Luis;Roush, William R.;Brown, Steven J.;Bokoch, Gary M.;Rosen, Hugh
NADPH氧化酶（Nox）蛋白催化活性氧（ROS）的受调控生成，活性氧在多种生理和病理生理过程中作为信号分子发挥关键作用。Nox家族的Nox1成员产生ROS对于细胞外基质（ECM）降解、富含肌动蛋白的被称为侵袭伪足的细胞结构的形成是必需的。与清除或抑制ROS产生相反，对Nox异构体的选择性抑制能够为这些细胞过程提供可逆的、机制方面的见解。目前尚未有特异性的Nox抑制剂被描述。在此，通过高通量筛选，我们鉴定出吩噻嗪的一个子集，2 - 乙酰基吩噻嗪（在此称为ML171）（及其相关的2 -（三氟甲基）- 吩噻嗪）是纳摩尔级、细胞活性的特异性Nox1抑制剂，它们能有效阻断Nox1依赖性的ROS生成，对其他细胞内产生ROS的酶和受体（包括其他Nox异构体）仅有微弱活性。ML171还能阻断结肠癌细胞中ECM降解侵袭伪足的ROS依赖性形成。这种效应可通过Nox1蛋白的过表达而逆转，这表明该化合物对Nox1具有选择性抑制机制。这些结果阐明了Nox1依赖性ROS生成在癌症侵袭机制中的相关性，并将ML171定义为一种有用的Nox1化学探针以及一种潜在的抑制癌细胞侵袭的治疗剂。
The NADPH oxidase (Nox) proteins catalyze the regulated formation of reactive oxygen species (ROS) which play key roles as signaling molecules in several physiological and pathophysiological processes. ROS generation by the Nox1 member of the Nox family is necessary for the formation of extracellular matrix (ECM)-degrading, actin-rich cellular structures known as invadopodia. Selective inhibition of Nox isoforms can provide reversible, mechanistic insights into these cellular processes in contrast to scavenging or inhibition of ROS production. Currently no specific Nox inhibitors have been described. Here, by high-throughput screening, we identify a sub-set of phenothiazines, 2-acetylphenothiazine (here referred to as ML171) (and its related 2-(trifluoromethyl)-phenothiazine) as nanomolar, cell-active and specific Nox1 inhibitors that potently block Nox1-dependent ROS generation, with only marginal activity on other cellular ROS-producing enzymes and receptors including the other Nox isoforms. ML171 also blocks the ROS-dependent formation of ECM-degrading invadopodia in colon cancer cells. Such effects can be reversed by overexpression of Nox1 protein, which is suggestive of a selective mechanism of inhibition of Nox1 by this compound. These results elucidate the relevance of Nox1-dependent ROS generation in mechanisms of cancer invasion, and define ML171 as a useful Nox1 chemical probe and a potential therapeutic agent for inhibition of cancer cell invasion.
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影响因子：
4.8
作者：
Cheng, Guangjie;Diebold, Becky A.;Lambeth, J. David
通讯作者：
Lambeth, J. David
DOI：
10.1073/pnas.90.10.4485
发表时间：
1993-05-15
影响因子：
11.1
作者：
LOWE, C;YONEDA, T;SORIANO, P
通讯作者：
SORIANO, P
影响因子：
3.3
作者：
Gianni, Davide;Bohl, Ben;Bokoch, Gary M.
通讯作者：
Bokoch, Gary M.
影响因子：
6.6
作者：
Blouw, Barbara;Seals, Darren F.;Courtneidge, Sara A.
通讯作者：
Courtneidge, Sara A.
影响因子：
7.5
作者：
Gimona, Mario;Buccione, Roberto;Linder, Stefan
通讯作者：
Linder, Stefan