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G-quadruplex-guided Cisplatin Triggers Multiple Pathways in Targeted Chemotherapy and Immunotherapy

CHEMICAL SCIENCE(2024)

Sun Yat Sen Univ

Cited 6|Views20
Abstract
G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [e.g., PyPDS (4-(2-aminoethoxy)-N2,N6-bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins. We found that cisplatin with PyPDS (CP) exhibits stronger specificity for covalent binding to G4 domains even in the presence of large amounts of dsDNA compared with PyPDS either extracellularly or intracellularly. Multiomics analysis reveals that CP can effectively regulate G4 functions, directly damage G4 structures, activate multiple antitumor signaling pathways, including the typical cGAS-STING pathway and AIM2-ASC pathway, trigger a strong immune response and lead to potent antitumor effects. These findings reflect that cisplatin-conjugated specific G4 targeting groups have antitumor mechanisms different from those of classic cisplatin and provide new strategies for the antitumor immunity of metals.
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要点】:本研究发现了G-四链体(G4)引导的顺铂通过激活多重通路在靶向化疗和免疫治疗中具有显著抗肿瘤效果,提出了一种新的金属抗肿瘤免疫策略。

方法】:通过将PyPDS与顺铂及其类似物结合,合成了三种铂复合物PyPDSplatins,并研究了其在细胞内外对G4结构的选择性结合能力及其对肿瘤细胞的影响。

实验】:实验使用了多种细胞系,通过多组学分析研究了PyPDS与顺铂结合物(CP)在调控G4功能、直接损伤G4结构、激活抗肿瘤信号通路(包括cGAS-STING和AIM2-ASC途径)以及引发强烈免疫反应方面的效果,发现了其具有强大的抗肿瘤效应。