👤 Li ZQ

Acute leukemia, a cancer originating in the bone marrow and blood-forming tissues, poses a significant threat to human health. Chemotherapy may cause a range of side effects and further cause greater suffering to the patients. Thus, reducing the toxicity of the drugs for treating leukemia has become a significant challenge. In this study, we developed two non‑platinum anticancer agents, ole-Ru and ole-Ir, by fusing the natural product oleanolic acid as the ligand into two metal (ruthenium and iridium) precursors. Ole-Ru and ole-Ir not only exhibited remarkable selectivity and cytotoxicity against NB4 cells through the apoptosis pathway, but also demonstrated low toxicity towards normal lung fibroblast cells, suggesting their potential for targeted treatment of acute leukemia cells. This work presents a rational design strategy for metal-based anticancer complexes aimed at inhibiting NB4 cells and expanded the scope of metallodrugs used in the treatment of leukemia. Show less

Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified, which limits their clinical application. Herein, we design a series of Ru(II) polypyridyl complexes containing bioactive β-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. The subsequent utilization of a photo-clickable probe, Ru5a, serves to validate the significance of ATP synthase as a crucial target for Ru5 through photoaffinity-based protein profiling. Ru5 accumulates in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, and influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates. Show less

Developing the cell-impermeable Ru(II) polypyridyl cationic complexes as effective photosensitizers (PS) which have high cellular uptake and photo-toxicity, but low dark toxicity, is quite challenging. Here we found that the highly reactive singlet oxygen (¹O₂) can be generated by the irradiation of a typical Ru(II) polypyridyl complex Ru(II)tris(tetramethylphenanthroline) ([Ru(TMP)₃]²⁺) under visible light irradiation by ESR with TEMPO (2,2,6,6-tetramethyl-4-piperidone-N-oxyl) as ¹O₂ probe. Effective cellular and nuclear delivery of cationic [Ru(TMP)₃]²⁺ was achieved through our recently developed ion-pairing method, and 2,3,4,5-tetrachlorophenol (2,3,4,5-TeCP) was found to be the most effective among all chlorophenols tested. The accelerated cellular, especially nuclear uptake of [Ru(TMP)₃]²⁺ results in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and DNA strand breaks, caspase 3/7 activation and cell apoptosis in HeLa cells upon light irradiation. More importantly, compared with other traditional photosensitizers, [Ru(TMP)₃]²⁺ showed significant photo-toxicity but low dark toxicity. Similar effects were observed when 2,3,4,5-TeCP was substituted by the currently clinically used anti-inflammatory drug flufenamic acid. This represents the first report that the cell-impermeable Ru(II) polypyridyl complex ion-paired with suitable lipophilic counter-anions functions as potent intracellular photosensitizer under visible light irradiation mainly via a ¹O₂-mediated mechanism. These findings should provide new perspectives for future investigations on other metal complexes with similar characteristics as promising photosensitizers for potential photodynamic therapy. Show less