摘要
背景与目的:肝细胞癌(HCC)是世界范围内癌症死亡的第二大原因.。在患者的基因毒性应激性往往导致较差的临床结果,并深入Nrf2 /上调相关的信号通路。在这项研究中,我们研究了两种indazolo [3,2-b]喹唑啉酮的抗癌活性之间的联系(IQ)的衍生物,iq-7和iq-12,及其对Nrf2信号通路/效果。 方法:我们最初测定iq-7和iq-12 Hep3B细胞(肝癌细胞)和肝(正常人肝细胞)的细胞系,并进一步检测Nrf2 /影响信号通路与细胞凋亡。 结果:iq-7和iq-12下调Nrf2及其下游靶基因的表达水平,如NQO1、HO-1和GCLC。在iq-7或iq-12对Hep3B细胞,线粒体膜电位下降而促凋亡蛋白VDAC1表达水平与抗凋亡蛋白Bcl-2分别显着的增加和减少。此外,iq-7(但不iq-12)诱导caspase-3活性。有趣的是,iq-7出现选择性地抑制Hep3B细胞同时具有对HL-7702细胞罕见的不良影响。 结论:两种化合物诱导凋亡和抑制Nrf2/ARE信号通路在肝癌细胞,并iq-7提出对癌细胞的特异度。这些化合物的设计可能因此代表设计的喹唑啉衍生物可以选择性地针对癌细胞的新策略。
关键词: 喹唑啉,喹唑啉酮,肝细胞癌,基因,细胞凋亡。
Current Molecular Medicine
Title:Indazolo[3,2-b]quinazolinones Attack Hepatocellular Carcinoma Hep3B Cells by Inducing Mitochondrial-Dependent Apoptosis and Inhibition of Nrf2/ARE Signaling Pathway
Volume: 16 Issue: 9
Author(s): Y. Zhang, R. Qiao, D. He, Z. Zhao, S. Yang, H. Zou, X. Zhang, M. Wu, J. Chen, P. Chen
Affiliation:
关键词: 喹唑啉,喹唑啉酮,肝细胞癌,基因,细胞凋亡。
摘要: Background and Objective: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Genotoxic stress resistance in patients often contributes to poor clinical outcomes, and is intensively associated to the upregulation of Nrf2/ARE signaling pathway. In this study, we examined the connection between the anticancer activity of two novel indazolo[3,2-b]quinazolinone (IQ) derivatives, IQ-7 and IQ-12, and their effect on the Nrf2/ARE signaling pathway.
Methods: We initially measured the cytotoxicity of IQ-7 and IQ-12 in Hep3B (human hepatoma cell) and HL-7702 (normal human liver cell) cell lines, then further detected their effects on Nrf2/ARE signaling pathway and apoptosis. Results: IQ-7 and IQ-12 downregulated the expression levels of Nrf2 and its downstream target genes, such as NQO1, HO-1 and Gclc. In Hep3B cells treated with IQ-7 or IQ-12, the mitochondrial membrane potential decreased dramatically while the expression level of the pro-apoptotic protein VDAC1 and anti-apoptotic protein Bcl-2 significantly increased and decreased, respectively. In addition, IQ-7 (but not IQ-12) also induced the activity of Caspase-3. Interestingly, IQ-7 appeared to selectively inhibit Hep3B cells while having rare adverse effect on HL-7702 cells. Conclusion: The two compounds were shown to induce apoptosis and inhibit the Nrf2/ARE signaling pathway in Hep3B cells, and IQ-7 was suggested a degree of specificity against cancer cells. The design of these compounds may therefore represent a new strategy for designing quinazoline derivatives that could selectively target carcinoma cells.Export Options
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Cite this article as:
Y. Zhang, R. Qiao, D. He, Z. Zhao, S. Yang, H. Zou, X. Zhang, M. Wu, J. Chen, P. Chen , Indazolo[3,2-b]quinazolinones Attack Hepatocellular Carcinoma Hep3B Cells by Inducing Mitochondrial-Dependent Apoptosis and Inhibition of Nrf2/ARE Signaling Pathway, Current Molecular Medicine 2016; 16 (9) . https://dx.doi.org/10.2174/1566524016666161128114444
DOI https://dx.doi.org/10.2174/1566524016666161128114444 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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