Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance.
Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance.
复制标题
器官化合物的结构调整允许氧化开关，以控制ER应力途径和绕过多药电阻。
DOI：
10.1039/c6sc00268d
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发表时间：
2016-07-01
期刊：
影响因子：
8.4
通讯作者：
Gaiddon C
中科院分区：
文献类型：
--
作者：
Chow MJ;Licona C;Pastorin G;Mellitzer G;Ang WH;Gaiddon C
改变有机钌化合物上的芳烃配体诱导ER应激途径的差异活化，导致非凋亡程序性细胞死亡并绕过耐药机制。多药耐药（MDR）是许多癌症类型化疗成功的主要障碍。一种特定的MDR机制是细胞存活途径的固有或获得性适应，其使恶性细胞对凋亡性细胞死亡具有抗性。由于大多数药物通过细胞凋亡起作用，因此能够诱导程序性细胞死亡（PCD）的替代形式的化合物可以潜在地用于绕过MDR。我们研究了两个有机钌络合物，RAS-1H和RAS-1 T，并证明，虽然他们都通过ER应激途径诱导非凋亡PCD，尽管适度的结构变化，他们的作用模式是截然不同的。RAS-1 T通过ROS介导的ER应激发挥作用，而RAS-1H不依赖于ROS。我们进一步表明，与包括奥沙利铂在内的临床药物相比，它们对肿瘤耐药细胞更有效。这项工作提供了基础ER应激调制使用金属配合物绕过凋亡阻力。
Varying the arene ligand on organoruthenium compounds induced the differential activation of ER stress pathways, leading to non-apoptotic programmed cell death and bypassing drug resistance mechanisms. Multidrug resistance (MDR) is a major impediment to the success of chemotherapy in many cancer types. One particular MDR mechanism is the inherent or acquired adaptation of the cellular survival pathways that render malignant cells resistant to apoptotic cell death. Since most drugs act through apoptosis, compounds capable of inducing alternative forms of programmed cell death (PCD) can potentially be harnessed to bypass MDR. We investigated two organoruthenium complexes, RAS-1H and RAS-1T, and demonstrated that although they both induced non-apoptotic PCD through ER stress pathways, their modes-of-action were drastically different despite modest structural variations. RAS-1T acted through ROS-mediated ER stress while RAS-1H was ROS-independent. We further showed that they were more efficacious against apoptosis-resistant cells compared to clinical drugs including oxaliplatin. This work provides the basis for underpinning ER stress modulation using metal complexes to bypass apoptosis resistance.
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影响因子：
4.9
作者：
Hanif, Muhammad;Nazarov, Alexey A.;Hartinger, Christian G.
通讯作者：
Hartinger, Christian G.
钌聚吡啶复合物通过靶向硫氧还蛋白还原酶诱导癌细胞中ROS介导的细胞凋亡
影响因子：
3.4
作者：
Luo, Zuandi;Yu, Lianling;Chen, Tianfeng
通讯作者：
Chen, Tianfeng
影响因子：
7.3
作者：
Marzano, Cristina;Pellei, Maura;Santini, Carlo
通讯作者：
Santini, Carlo
癌细胞中的DNA甲基化和凋亡性。
影响因子：
6
作者：
Hervouet E;Cheray M;Vallette FM;Cartron PF
通讯作者：
Cartron PF
影响因子：
4.1
作者：
Librizzi, Mariangela;Longo, Alessandra;Luparello, Claudio
通讯作者：
Luparello, Claudio