Details

Autor(en) / Beteiligte

• Ma, Tian-Zhu
• Liu, Liu-Yi
• Zeng, You-Liang
• Ding, Ke
• Zhang, Hang
• Liu, Wenting
• Cao, Qian
• Xia, Wei
• Xiong, Xushen
• Wu, Chao
• Mao, Zong-Wan

Titel

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

Ist Teil von

• Chemical science (Cambridge), 2024-06, Vol.15 (25), p.9756-9774

Ort / Verlag

Cambridge: Royal Society of Chemistry

Erscheinungsjahr

2024

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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)- N 2 , N 6 -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. PyPDSplatins can not only bind G4s to repress c-MYC and VEGF expressions but also damage G4s to activate the immune-related cGAS-STING pathway and AIM2-ASC-related pyroptosis, triggering a strong immune response and potent antitumor effects.