Biotin-Targeted Au(I) Radiosensitizer for Cancer Synergistic Therapy by Intervening with Redox Homeostasis and Inducing Ferroptosis,Journal of Medicinal Chemistry

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Biotin-Targeted Au(I) Radiosensitizer for Cancer Synergistic Therapy by Intervening with Redox Homeostasis and Inducing Ferroptosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-10 , DOI: 10.1021/acs.jmedchem.2c00300
Zhibin Yang _{1,

2} , Sheng Huang ₁ , Yu Liu ₁ , Xingyu Chang ₁ , Yanshan Liang ₁ , Xi Li ₃ , Zhongren Xu ₁ , Shiyu Wang ₃ , Yunlong Lu ₁ , Yuan Liu ₃ , Wukun Liu _{1,

4}

Affiliation

The search for highly selective sensitizers with a novel mechanism for tumor targeting therapy is of considerable interest. In this work, we have developed a series of new biotin-targeted Au(I) complexes. Through systematic biological evaluation and comparison, biotinylated Au(I) complex 3a containing a triphenylphosphine ligand was screened, as it realized both prominent efficient inhibition and selective cytotoxicity to cancer cells, and the effect was better than that of popularly used auranofin. Meanwhile, complex 3a, as a potent radiosensitizer, enhances anticancer effects in vitro and in vivo and has sensitization selectivity. From the action mechanism study, we provide evidence that complex 3a could intervene in redox homeostasis through targeted binding and strong suppression of thioredoxin reductase (TrxR) and induce the ferroptosis death process, enabling it to sensitize tumor cells to radiotherapy. Thus, complex 3a has enormous potential as an efficient and specific radiosensitizing agent in cancer therapy.

中文翻译：

生物素靶向 Au(I) 放射增敏剂通过干预氧化还原稳态和诱导铁死亡进行癌症协同治疗

寻找具有肿瘤靶向治疗新机制的高选择性增敏剂具有相当大的兴趣。在这项工作中，我们开发了一系列新的生物素靶向 Au(I) 复合物。通过系统的生物学评价和比较，筛选出含有三苯基膦配体的生物素化Au(I)配合物3a，对癌细胞具有显着的高效抑制和选择性细胞毒性，且效果优于常用的金诺芬。同时，络合物3a作为一种有效的放射增敏剂，可增强体内外抗癌作用，并具有增敏选择性。从作用机制研究中，我们提供的证据表明复合物3a可以通过靶向结合和强烈抑制硫氧还蛋白还原酶（TrxR）来干预氧化还原稳态，并诱导铁死亡过程，使其能够使肿瘤细胞对放射治疗敏感。因此，复合物3a在癌症治疗中作为一种有效且特异性的放射增敏剂具有巨大的潜力。

更新日期：2022-06-10

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