DNA-Damage-Response-Targeting Mitochondria-Activated Multifunctional Prodrug Strategy for Self-Defensive Tumor Therapy

Paramesh Jangili, Na Kong, Ji Hyeon Kim, Jun Zhou, Haijun Liu, Xingcai Zhang, Wei Tao, Jong Seung Kim

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article numbere202117075
JournalAngewandte Chemie - International Edition
Volume61
Issue number16
DOIs
Publication statusPublished - 2022 Apr 11

Keywords

  • DNA Damage Response
  • DNA Repair
  • Drug Delivery
  • Floxuridine
  • Protein Phosphatase 2A

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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