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

20 Citations (Scopus)

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

Bibliographical note

Funding 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.).

Publisher Copyright:
© 2022 Wiley-VCH GmbH.

Keywords

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

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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