Apoptosis-independent organoruthenium anticancer complexes that overcome multidrug resistance: self-assembly and phenotypic screening strategies.
Apoptosis-independent organoruthenium anticancer complexes that overcome multidrug resistance: self-assembly and phenotypic screening strategies.
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DOI：
10.1039/c7sc00497d
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发表时间：
2017-05-01
期刊：
影响因子：
8.4
通讯作者：
Ang WH
中科院分区：
文献类型：
--
作者：
Chow MJ;Alfiean M;Pastorin G;Gaiddon C;Ang WH
对组合自组装有机钌络合物文库的表型筛选揭示了通过非依赖性途径作用于难治性癌症的构建体。多药耐药性是化疗的主要障碍，并限制了常规抗癌药物的疗效。绕过多药耐药性的策略是开发能够诱导非凋亡依赖性程序性细胞死亡的新候选药物。然而，涉及替代性程序性细胞死亡的细胞途径尚未得到很好的阐明，并且是多因素的，这使得基于靶点的发现方法成为一个挑战。在这里，我们表明，一个协调指导的三组分组装和表型筛选策略可以作为一个可行的替代方案，用于识别非肿瘤独立的有机钌抗癌剂。通过板上合成和筛选的195有机钌配合物对肿瘤敏感和耐药的癌症，我们确定了两个肿瘤独立的命中。随后对两个命中的验证显示缺乏凋亡生物标志物的诱导、半胱天冬酶非依赖性活性以及在结肠癌敏感性和耐药性结肠直肠癌中的同等功效。这验证了它们的非肿瘤依赖性作用模式，为治疗高度难治性癌症表型的潜在候选者铺平了道路。
Phenotypic screening on a library of combinatorial self-assembled organoruthenium complexes revealed constructs that act on refractory cancers via apoptosis-independent pathways. Multidrug resistance is a major impediment to chemotherapy and limits the efficacies of conventional anticancer drugs. A strategy to bypass multidrug resistance is to develop new drug candidates capable of inducing apoptosis-independent programmed cell death. However, cellular pathways implicated in alternative programmed cell death are not well-elucidated and multifactorial, making a target-based discovery approach a challenge. Here, we show that a coordination-directed three-component assembly and phenotypic screening strategy could be employed as a viable alternative for the identification of apoptosis-independent organoruthenium anticancer agents. Through an on-plate synthesis and screening of 195 organoruthenium complexes against apoptosis-sensitive and -resistant cancers, we identified two apoptosis-independent hits. Subsequent validation of the two hits showed a lack of induction of apoptotic biomarkers, a caspase-independent activity and an equal efficacy in both apoptosis-sensitive and -resistant colorectal cancers. This validated their apoptosis-independent modes-of-action, paving the way as potential candidates for the treatment of highly-refractory cancer phenotypes.
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影响因子：
16.6
作者：
Soldevila-Barreda, Joan J.;Romero-Canelon, Isolda;Habtemariam, Abraha;Sadler, Peter J.
通讯作者：
Sadler, Peter J.
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。
影响因子：
8.4
作者：
Chow MJ;Licona C;Pastorin G;Mellitzer G;Ang WH;Gaiddon C
通讯作者：
Gaiddon C
影响因子：
15
作者：
Suntharalingam K;Awuah SG;Bruno PM;Johnstone TC;Wang F;Lin W;Zheng YR;Page JE;Hemann MT;Lippard SJ
通讯作者：
Lippard SJ
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