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.
Bibliographical noteFunding Information:
This work was supported by the CRI project (2018R1A3B1052702, J.S.K.), the Korea University Grant (P.J.), National Natural Science Foundation of China (82122076, N.K.), US METAvivor Early Career Investigator Award (2018A020560, W.T.), Harvard Medical School/Brigham and Women's Hospital Department Basic Scientist Grant (2420 BPA075, W.T.), Farokhzad Family Distinguished Chair Foundation (W.T.), and Center for Nanomedicine Research Fund (2019A014810, W.T.).
© 2022 Wiley-VCH GmbH.
- DNA Damage Response
- DNA Repair
- Drug Delivery
- Protein Phosphatase 2A
ASJC Scopus subject areas