Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic^® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

Graphical abstract

中文翻译：

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用 pluronic® F-127 封装的溶酶体靶向钌 (II) 复合物可诱导 A549 细胞发生肿瘤

过渡金属配合物具有独特的纳米颗粒包装特性和显着的癌细胞毒性，已成为铂类抗肿瘤药物的潜在替代品。在这里，我们报告了三种引入 5-氟尿嘧啶衍生配体的新型钌配合物的合成、表征和抗肿瘤活性。值得注意的是，将一种此类金属络合物Ru3封装在 pluronic ^® F-127 胶束 ( Ru3-M )中，可将Ru3对 A549 细胞的细胞毒性显着增强四倍。为了确定Ru3-M细胞毒性的机制，进行了额外的体外实验，结果表明，用靶向溶酶体的Ru3-M处理 A549 细胞会引发氧化应激，诱导线粒体膜电位去极化，并大幅降低细胞内 ATP 水平。总而言之，这些结果表明Ru3-M主要通过一种称为肿瘤作用的非凋亡途径杀死细胞，观察到的Ru3-M诱导的细胞形态变化（包括细胞质冲洗、细胞肿胀和细胞质空泡形成）证明了这一点。反过来，这些变化共同导致细胞骨架崩溃并激活具有已知胶体渗透功能的 porimin 和 calpain1 蛋白，这些功能将这种胶体渗透过程与其他细胞死亡过程区分开来。总之，Ru3-M是一种潜在的抗癌剂，可通过 Ru(II) 复合物通过肿瘤作用触发细胞死亡的新机制杀死 A549 细胞。

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