Brás Ana Rita, Fernandes Pedro, Moreira Tiago, Morales-Sanfrutos Julia, Sabidó Eduard, Antunes Alexandra M M, Valente Andreia, Preto Ana
Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Institute of Science and Innovation for Bio-Sustainability (IB-S), University of Minho, 4710-057 Braga, Portugal.
Pharmaceutics. 2023 Jun 14;15(6):1731. doi: 10.3390/pharmaceutics15061731.
Colorectal cancer (CRC) is among the most deadly cancers worldwide. Current therapeutic strategies have low success rates and several side effects. This relevant clinical problem requires the discovery of new and more effective therapeutic alternatives. Ruthenium drugs have arisen as one of the most promising metallodrugs, due to their high selectivity to cancer cells. In this work we studied, for the first time, the anticancer properties and mechanisms of action of four lead Ru-cyclopentadienyl compounds, namely , , and , in two CRC-derived cell lines (SW480 and RKO). Biological assays were performed on these CRC cell lines to evaluate cellular distribution, colony formation, cell cycle, proliferation, apoptosis, and motility, as well as cytoskeleton and mitochondrial alterations. Our results show that all the compounds displayed high bioactivity and selectivity, as shown by low half-maximal inhibitory concentrations (IC) against CRC cells. We observed that all the Ru compounds have different intracellular distributions. In addition, they inhibit to a high extent the proliferation of CRC cells by decreasing clonogenic ability and inducing cell cycle arrest. , , and also induce apoptosis, increase the levels of reactive oxygen species, lead to mitochondrial dysfunction, induce actin cytoskeleton alterations, and inhibit cellular motility. A proteomic study revealed that these compounds cause modifications in several cellular proteins associated with the phenotypic alterations observed. Overall, we demonstrate that Ru compounds, especially and , display promising anticancer activity in CRC cells with a high potential to be used as new metallodrugs for CRC therapy.
结直肠癌（CRC）是全球最致命的癌症之一。目前的治疗策略成功率低且有多种副作用。这一相关临床问题需要发现新的、更有效的治疗选择。钌药物因其对癌细胞的高选择性，已成为最有前景的金属药物之一。在这项工作中，我们首次研究了四种先导钌 - 环戊二烯基化合物，即 、 、 和 ，在两种结直肠癌衍生细胞系（SW480和RKO）中的抗癌特性及作用机制。对这些结直肠癌细胞系进行了生物学检测，以评估细胞分布、集落形成、细胞周期、增殖、凋亡和迁移能力，以及细胞骨架和线粒体改变。我们的结果表明，所有化合物均表现出高生物活性和选择性，对结直肠癌细胞的半数最大抑制浓度（IC）较低即证明了这一点。我们观察到所有钌化合物具有不同的细胞内分布。此外，它们通过降低克隆形成能力和诱导细胞周期停滞，在很大程度上抑制了结直肠癌细胞的增殖。 、 和 还诱导凋亡、增加活性氧水平、导致线粒体功能障碍、诱导肌动蛋白细胞骨架改变并抑制细胞迁移。一项蛋白质组学研究表明，这些化合物会导致与所观察到的表型改变相关的几种细胞蛋白发生修饰。总体而言，我们证明钌化合物，尤其是 和 ，在结直肠癌细胞中显示出有前景的抗癌活性，具有很高的潜力可作为结直肠癌治疗的新型金属药物。
