Abstract
We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.
Original language | English |
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Article number | e202117075 |
Journal | Angewandte Chemie - International Edition |
Volume | 61 |
Issue number | 16 |
DOIs | |
Publication status | Published - 2022 Apr 11 |
Bibliographical note
Publisher Copyright:© 2022 Wiley-VCH GmbH.
Keywords
- DNA Damage Response
- DNA Repair
- Drug Delivery
- Floxuridine
- Protein Phosphatase 2A
ASJC Scopus subject areas
- Catalysis
- General Chemistry