Issue 25, 2024

G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy

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.

Graphical abstract: G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy

Supplementary files

Article information

Article type
Edge Article
Submitted
27 Jan 2024
Accepted
09 May 2024
First published
15 May 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 9756-9774

G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy

T. Ma, L. Liu, Y. Zeng, K. Ding, H. Zhang, W. Liu, Q. Cao, W. Xia, X. Xiong, C. Wu and Z. Mao, Chem. Sci., 2024, 15, 9756 DOI: 10.1039/D4SC00643G

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