Cycloruthenated Self-Assembly with Metabolic Inhibition to Efficiently Overcome Multidrug Resistance in Cancers

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.

Automated summary

RuZ, a cycloruthenated complex, self-assembles into nanoaggregates in cell culture medium, leading to high intracellular concentrations in multi-drug resistant (MDR) cancer cells. It decreases oxygen consumption, inhibits glycolysis, lowers ATP levels, increases retention in MDR cells, induces oxidative stress and apoptosis. Proteomic analysis shows RuZ decreases glycolysis and mitochondrial respiration proteins while increasing apoptosis-related proteins. It inhibits proliferation of 35 cancer cell lines, including drug-resistant ones, and is effective in doxorubicin-resistant mouse tumor xenografts.