Mitophagy is an important target for antitumor drugs development. A series of ciclopirox (CPX) platinum(IV) hybrids targeting PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitophagy were designed and prepared as antitumor agents. The dual CPX platinum(IV) complex with cisplatin core was screened out as a candidate, which displayed promising antitumor activities both in vitro and in vivo. Mechanistically, it caused serious DNA damage in tumor cells. Then, remarkable mitochondrial damage was induced accompanied by the mitochondrial membrane depolarization and reactive oxygen species generation, which further promoted apoptosis through the Bcl-2/Bax/Caspase3 pathway. Furthermore, mitophagy was ignited via the PINK1/Parkin/P62/LC3 axis, and exhibited positive influence on promoting the apoptosis of tumor cells. The antitumor immunity was boosted by the block of immune check point programmed cell death ligand-1 (PD-L1), which further increased the density of T cells in tumors. Subsequently, the metastasis of tumor cells was inhibited by inhibiting angiogenesis in tumors.

中文翻译：

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环吡酮铂 （IV） 偶联物通过促进线粒体自噬和激发免疫反应来抑制肿瘤


线粒体自噬是抗肿瘤药物开发的重要靶点。设计并制备了一系列靶向 PTEN 诱导的推定激酶 1 （PINK1）/Parkin 介导的线粒体自噬的环吡酮 （CPX） 铂 （IV） 杂交体作为抗肿瘤药物。筛选出具有顺铂核心的双 CPX 铂 （IV） 复合物作为候选，在体外和体内均显示出良好的抗肿瘤活性。从机制上讲，它在肿瘤细胞中造成了严重的 DNA 损伤。然后，诱导显着的线粒体损伤，伴随着线粒体膜去极化和活性氧的产生，通过 Bcl-2/Bax/Caspase3 通路进一步促进细胞凋亡。此外，线粒体自噬通过 PINK1/Parkin/P62/LC3 轴被点燃，并表现出对促进肿瘤细胞凋亡的积极影响。阻断免疫检查点程序性细胞死亡配体-1 （PD-L1） 增强了抗肿瘤免疫力，进一步增加了肿瘤中 T 细胞的密度。随后，通过抑制肿瘤中的血管生成来抑制肿瘤细胞的转移。