Q39, a novel synthetic Quinoxaline 1,4-Di-N-oxide compound with anti-cancer activity in hypoxia
Q39, a novel synthetic Quinoxaline 1,4-Di-N-oxide compound with anti-cancer activity in hypoxia
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Q39，一种新型合成喹喔啉 1,4-二氧化氮化合物，在缺氧条件下具有抗癌活性
DOI：
10.1016/j.ejphar.2007.12.006
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发表时间：
2008-03-10
影响因子：
5
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Weng, Qinjie;Wang, Duoduo;Yang, Bo
缺氧是各种肿瘤不可避免的生存环境之一，导致肿瘤对放疗、化疗产生抵抗。由喹喔啉1，4-二氮氧化物（Quinoxaline 1，4-Di-N-oxide）衍生得到的3-（4-bromophenyl）-2-（ethylsulfonyl）-6-methylquinoxaline 1，4-dioxide（Q39）在缺氧条件下具有较高的抗癌活性。细胞毒性试验表明，Q39在所有测试的细胞系中都是一种潜在且高效的抗癌化合物，在缺氧条件下IC 50值为0.18 +/- 0.03-8.88 +/- 1.12 μ M，在常氧条件下IC 50值为0.33 +/- 0.04-8.74 +/- 1.28 μ M。在接下来的研究中，我们证实了Q39可以诱导K562细胞凋亡，并呈时间依赖性。荧光染色法观察到Q39诱导K562细胞缺氧时线粒体膜电位（Delta Psi（m））降低。Western blotting结果显示，Q39可降低缺氧时缺氧诱导因子-1 α（HIF-1 alpha）和血管内皮生长因子（VEGF）的蛋白表达。该化合物引起caspase-3的激活和随后的切割其底物聚（ADP-核糖）聚合酶（PARP）在缺氧。Q39可上调K562细胞Bax的表达，下调Bcl-2的表达。Q39还影响与线粒体诱导的凋亡相关的促分裂原活化蛋白激酶（MAPK）和其他蛋白的表达。此外，Q39介导的细胞凋亡在用JNK特异性抑制剂处理后没有逆转。综上所述，本研究表明Q39是一种新的抗缺氧癌细胞的化合物。Bcl-2蛋白家族和MAPKs介导的线粒体信号通路和HIF-1信号通路可能参与了Q39诱导的细胞凋亡。(C)2007 Elsevier B. V.保留所有权利。
Hypoxia is one of the inevitable circumstances in various tumors and results in tumor resistance to radiotherapy and chemotherapy. The present data showed that 3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide (Q39), derived from Quinoxaline 1,4-Di-N-oxide, possessed high anti-cancer activity in hypoxia. Cytotoxicity assay demonstrated that Q39 is a potential and high efficient anti-cancer compound in all tested cell lines with IC50 values of 0.18 +/- 0.03-8.88 +/- 1.12 mu M in hypoxia and 0.33 +/- 0.04-8.74 +/- 1.28 mu M in normoxia. In the following work concerning the mechanism of Q39 in hypoxia, we confirmed that Q39 could cause the apoptosis of K562 cells in a time-dependent manner. By fluorescence stain assay, Q39-induced mitochondria membrane potential (Delta Psi(m)) loss was observed in K562 cells in hypoxia. Based on the western blotting, Q39 decreased the protein expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) in hypoxia. The compound caused the activation of caspase-3 and subsequent cleavage of its substrate poly (ADP-ribose) polymerase (PARP) in hypoxia. Meanwhile, we found the upregulation of Bax by Q39 in K562 cells as well as the downregulation of Bcl-2. Q39 also influenced the expression of Mitogen-Activated Protein Kinase (MAPKs) and other proteins relative to mitochondria induced apoptosis. In addition, Q39-mediated apoptosis was not reversed after treatment with the JNK-specific inhibitor. In summary, the present study demonstrated Q39 was a novel compound against cancer cells in hypoxia. The mitochondrial pathway mediated by Bcl-2 protein family and MAPKs and the HIF-1 pathway might be involved in signaling Q39-induced apoptosis. (C) 2007 Elsevier B.V. All rights reserved.