Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma.
Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1021/acs.jmedchem.7b01463
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发表时间：
2018-02-22
影响因子：
7.3
通讯作者：
Neamati N
中科院分区：
文献类型：
--
作者：
Kuang Y;Sechi M;Nurra S;Ljungman M;Neamati N
改变氧化还原稳态为胰腺癌的治疗提供了独特的治疗机会。喹唑啉二酮类化合物（QDs）是一种新型的氧化还原调节剂，我们以前发现它可以诱导胰腺导管腺癌（PDAC）细胞株的有效生长抑制。我们的先导优化活动产生了QD325作为最有效的氧化还原调节剂候选物，其在PDAC细胞中诱导大量活性氧（ROS）。用QD化合物处理后的新生RNA测序揭示了胰腺癌细胞的细胞核、内质网和线粒体中的应激反应的诱导。此外，QD化合物诱导Nrf2介导的氧化应激和未折叠蛋白质应答，如代表性基因如NQO1、HMOX1、DDIT 3和HSPA5的RNA合成的剂量依赖性增加所证明的。在较高浓度下，量子点通过抑制mtDNA转录和下调mtDNA编码的OXPHOS酶来阻断线粒体功能。重要的是，用QD325治疗在体内耐受性良好，并显著延迟小鼠中的肿瘤生长。我们的研究支持QD325作为治疗PDAC的新疗法的开发。
Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose dependent increases in RNA synthesis of representative genes such as NQO1, HMOX1, DDIT3 and HSPA5. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with QD325 were well tolerated in vivo and significantly delayed tumor growth in mice. Our study supports the development of QD325 as a new therapeutic in the treatment of PDAC.
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DOI：
10.1038/ajg.2016.610
发表时间：
2017-04
期刊：
The American journal of gastroenterology
影响因子：
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作者：
Fogel EL;Shahda S;Sandrasegaran K;DeWitt J;Easler JJ;Agarwal DM;Eagleson M;Zyromski NJ;House MG;Ellsworth S;El Hajj I;O'Neil BH;Nakeeb A;Sherman S
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DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
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影响因子：
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作者：
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作者：
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通讯作者：
Reindl, Katie M