Activation of the c-Jun N-terminal kinase/activating transcription factor 3 (ATF3) pathway characterizes effective arylated diazeniumdiolate-based nitric oxide-releasing anticancer prodrugs.
Activation of the c-Jun N-terminal kinase/activating transcription factor 3 (ATF3) pathway characterizes effective arylated diazeniumdiolate-based nitric oxide-releasing anticancer prodrugs.
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DOI：
10.1021/jm2004128
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发表时间：
2011-11-24
影响因子：
7.3
通讯作者：
Saavedra, Joseph E.
中科院分区：
文献类型：
--
作者：
Maciag, Anna E.;Nandurdikar, Rahul S.;Hong, Sam Y.;Chakrapan, Harinath;Diwan, Bhalchandra;Morris, Nicole L.;Shami, Paul J.;Shiao, Yih-Horng;Anderson, Lucy M.;Keefer, Larry K.;Saavedra, Joseph E.
对于非小细胞肺癌，需要改进的治疗方法。基于二醇二氮鎓的一氧化氮（NO）释放前药是一类越来越有前途的基于NO的治疗剂。最近，我们已经证明O2-（2，4-二硝基苯基）1-[（4-乙氧羰基）哌嗪-1-基]二氮烯-1-鎓-1，2-二醇盐（JS-K，1）在培养和体内对非小细胞肺癌（NSCLC）细胞有效。在这里，我们报告的机制研究与化合物1及其高哌嗪类似物，和这些更稳定的前药的结构修饰。化合物1及其高哌嗪类似物是体外和体内针对NSCLC细胞的有效细胞毒性剂，伴随着SAPK/JNK应激途径的激活和其下游效应物ATF 3的上调。这些事件发生后细胞凋亡。一个芳基取代的类似物，尽管在谷胱甘肽的存在下延长半衰期，没有激活JNK或具有抗肿瘤活性。这些数据表明，与谷胱甘肽的反应速率和JNK/ATF 3的活化是这些前药杀死癌细胞的决定因素。
Improved therapies are needed for non-small cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)–releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against non-small cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue, and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have anti-tumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.
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影响因子：
8
作者：
Syed, V;Mukherjee, K;Ho, SM
通讯作者：
Ho, SM
影响因子：
56.9
作者：
Tournier, C;Hess, P;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
3.5
作者：
Papadakis, ES;Finegan, KG;Tournier, C
通讯作者：
Tournier, C
影响因子：
5.3
作者：
Chen, Shih-Chung;Liu, Yu-Chi;Wang, Danny Ling
通讯作者：
Wang, Danny Ling
影响因子：
7.3
作者：
Shami, Paul J.;Saavedra, Joseph E.;Keefer, Larry K.
通讯作者：
Keefer, Larry K.