The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C^∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

中文翻译：

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基于异喹啉生物碱的环铂 (II) 复合物可在三阴性乳腺癌细胞中引发铁蛋白自噬依赖性铁死亡

具有新型细胞毒机制的金属基抗癌药物的开发和优化已成为克服化疗耐药性和副作用的关键策略。同时诱导铁死亡和自噬死亡的药物作为癌症治疗的潜在方式受到了广泛的关注。然而，只有有限的药物或治疗方式可以协同诱导铁死亡和自噬性肿瘤细胞死亡。在这项工作中，我们设计并合成了四种带有异喹啉生物碱 C ^∧ N 配体的新型环铂 (II) 配合物。在筛选这些药物的体外活性时，我们发现与顺铂相比，Pt-3表现出更高的细胞毒性选择性、更低的耐药因子和更高的抗癌活性。此外，我们证明Pt-3可以引发有效的铁蛋白自噬依赖性铁死亡，在体内表现出比顺铂更低的毒性和更好的治疗活性。我们的结果表明Pt-3是癌症治疗中进一步药物开发的有前途的候选者或范例。