Guangdong Provincial Key Laboratory of Digestive Cancer Research, Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, P. R. China.
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P. R. China.
Adv Mater. 2022 Jan;34(1):e2100245. doi: 10.1002/adma.202100245. Epub 2021 Oct 24.
The synthesis and the evaluation of the efficacy of a cycloruthenated complex, RuZ, is reported, to overcome multi-drug resistance (MDR) in cancer cells. RuZ can self-assemble into nanoaggregates in the cell culture medium, resulting in a high intracellular concentration of RuZ in MDR cancer cells. The self-assembly significantly decreases oxygen consumption and inhibits glycolysis, which decreases cellular adenosine triphosphate (ATP) levels. The decrease in ATP levels and its low affinity for the ABCB1 and ABCG2 transporters (which mediate MDR) significantly increase the retention of RuZ by MDR cancer cells. Furthermore, RuZ increases cellular oxidative stress, inducing DNA damage, and, in combination with the aforementioned effects of RuZ, increases the apoptosis of cancer cells. Proteomic profiling analysis suggests that the RuZ primarily decreases the expression of proteins that mediate glycolysis and aerobic mitochondrial respiration and increases the expression of proteins involved in apoptosis. RuZ inhibits the proliferation of 35 cancer cell lines, of which 7 cell lines are resistant to clinical drugs. It is also active in doxorubicin-resistant MDA-MB-231/Adr mouse tumor xenografts. To the best of our knowledge, the results are the first to show that self-assembled cycloruthenated complexes are efficacious in inhibiting the growth of MDR cancer cells.
本文报道了一种环钌配合物 RuZ 的合成及其功效评价，旨在克服癌细胞的多药耐药性（MDR）。RuZ 可以在细胞培养液中自组装成纳米聚集体，从而使 MDR 癌细胞内的 RuZ 浓度升高。这种自组装显著降低了氧耗和糖酵解，导致细胞内三磷酸腺苷（ATP）水平降低。ATP 水平的降低及其与 ABCB1 和 ABCG2 转运蛋白（介导 MDR）的低亲和力，使 RuZ 被 MDR 癌细胞的保留显著增加。此外，RuZ 增加了细胞氧化应激，诱导 DNA 损伤，并与 RuZ 的上述作用相结合，增加了癌细胞的凋亡。蛋白质组学分析表明，RuZ 主要降低了介导糖酵解和有氧线粒体呼吸的蛋白质的表达，同时增加了参与凋亡的蛋白质的表达。RuZ 抑制了 35 种癌细胞系的增殖，其中 7 种细胞系对临床药物有耐药性。它在多柔比星耐药 MDA-MB-231/Adr 小鼠肿瘤异种移植模型中也具有活性。据我们所知，这些结果首次表明自组装的环钌配合物在抑制 MDR 癌细胞生长方面是有效的。
