Ruthenium and osmium complexes have been shown to bypass several resistance mechanisms of platinum anticancer drugs, suggesting that they might represent therapeutic alternatives. However, the resistance mechanisms that may alter the cytotoxicity of ruthenium and osmium complexes have not been identified yet. Here we investigated the mechanisms governing the variability in the cytotoxicity of two ruthenium cyclometalated compounds and their osmium equivalents. We characterized their anticancer properties in vitro and in vivo, and we developed a 4-step approach to identify genes involved in their sensibility/resistance by correlating their cytotoxicity measures with transcriptomic data of 60 cancer cell lines. As previously observed for ruthenium complexes, we showed that osmium compounds target the endoplasmic reticulum stress pathway and that their activity was not hindered by mutation in the tumor suppressor gene TP53. Then, we identified multiple sensibility/resistance genes that correlated with the cytotoxicity of cyclometalated compounds. Docking and functional studies demonstrated that inhibition of some of these resistance mechanisms, namely ABCB1 export and EGFR expression, improved the activity of cyclometalated complexes. Interestingly, switching from ruthenium to osmium favored cytotoxicity while reducing sensibility to the ABCB1 export mechanism. In summary, this study represents the first comprehensive investigation of the resistance mechanisms that alter the biological activity of ruthenium or osmium complexes, and identifies some of the chemical determinants that are important for their activity.

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钌和环金属化化合物的抗癌活性：ABCB1和EGFR的鉴定为耐药机制

钌和配合物已被证明绕开了铂类抗癌药的几种耐药机制，这表明它们可能代表了替代治疗方法。然而，尚未发现可能改变钌和复合物的细胞毒性的抗性机制。在这里，我们研究了两种钌金属环化钌化合物及其当量的细胞毒性变化规律。我们表征了它们在体外和体内的抗癌特性，并且我们开发了一种四步方法，通过将其细胞毒性指标与60个癌细胞系的转录组数据相关联，来鉴定涉及其敏感性/抗性的基因。如先前对于钌配合物所观察到的，我们表明化合物靶向内质网应激途径，并且其活性不受肿瘤抑制基因TP53突变的阻碍。然后，我们鉴定了多个与环金属化化合物的细胞毒性相关的敏感性/抗性基因。对接和功能研究表明，抑制其中一些抗性机制（即ABCB1输出和EGFR表达）可改善环金属化复合物的活性。有趣的是，从钌转换为有利于细胞毒性，同时降低了对ABCB1出口机制的敏感性。