Reigan Philip, Colucci Marie A, Siegel David, Chilloux Aurélie, Moody Christopher J, Ross David
Department of Pharmaceutical Sciences and Cancer Center, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262, USA.
Biochemistry. 2007 May 22;46(20):5941-50. doi: 10.1021/bi700008y. Epub 2007 Apr 25.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is currently an emerging target in pancreatic cancer. In this report, we describe a series of indolequinones, based on 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), and evaluate NQO1 inhibition and growth inhibitory activity in the human pancreatic MIA PaCa-2 tumor cell line. The indolequinones with 4-nitrophenoxy, 4-pyridinyloxy, and acetoxy substituents at the (indol-3-yl)methyl position were NADH-dependent inhibitors of recombinant human NQO1, indicative of mechanism-based inhibition. However, those with hydroxy and phenoxy substituents were poor inhibitors of NQO1 enzyme activity, due to attenuated elimination of the leaving group. The ability of this series of indolequinones to inhibit recombinant human NQO1 correlated with NQO1 inhibition in MIA PaCa-2 cells. The examination of indolequinone interactions in complex with NQO1 from computational-based molecular docking simulations supported the observed biochemical data with respect to NQO1 inhibition. The design of both NQO1-inhibitory and noninhibitory indolequinone analogues allowed us to test the hypothesis that NQO1 inhibition was required for growth inhibitory activity in MIA PaCa-2 cells. ES936 and its 6-methoxy analogue were potent inhibitors of NQO1 activity and cell proliferation; however, the 4-pyridinyloxy and acetoxy compounds were also potent inhibitors of NQO1 activity but relatively poor inhibitors of cell proliferation. In addition, the phenoxy compounds, which were not inhibitors of NQO1 enzymatic activity, demonstrated potent growth inhibition. These data demonstrate that NQO1 inhibitory activity can be dissociated from growth inhibitory activity and suggest additional or alternative targets to NQO1 that are responsible for the growth inhibitory activity of this series of indolequinones in human pancreatic cancer.
烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：醌氧化还原酶1（NQO1）目前是胰腺癌中一个新兴的靶点。在本报告中，我们描述了一系列基于5-甲氧基-1,2-二甲基-3-[(4-硝基苯氧基)甲基]吲哚-4,7-二酮（ES936）的吲哚醌，并评估了它们对人胰腺MIA PaCa-2肿瘤细胞系中NQO1的抑制作用和生长抑制活性。在（吲哚-3-基）甲基位置带有4-硝基苯氧基、4-吡啶氧基和乙酰氧基取代基的吲哚醌是重组人NQO1的NADH依赖性抑制剂，表明其为基于机制的抑制作用。然而，带有羟基和苯氧基取代基的吲哚醌对NQO1酶活性的抑制作用较差，这是由于离去基团的消除减弱所致。这一系列吲哚醌抑制重组人NQO1的能力与它们对MIA PaCa-2细胞中NQO1的抑制作用相关。基于计算的分子对接模拟对吲哚醌与NQO1复合物相互作用的研究支持了所观察到的关于NQO1抑制作用的生化数据。NQO1抑制性和非抑制性吲哚醌类似物的设计使我们能够检验这样一个假设，即MIA PaCa-2细胞的生长抑制活性需要NQO1抑制作用。ES936及其6-甲氧基类似物是NQO1活性和细胞增殖的有效抑制剂；然而，4-吡啶氧基和乙酰氧基化合物也是NQO1活性的有效抑制剂，但对细胞增殖的抑制作用相对较差。此外，不是NQO1酶活性抑制剂的苯氧基化合物表现出强效的生长抑制作用。这些数据表明，NQO1抑制活性可以与生长抑制活性分离，并提示在这一系列吲哚醌对人胰腺癌的生长抑制活性中，除NQO1外还存在其他或替代靶点。
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