Related Experiment Video

Updated: Sep 20, 2025

Fluorescence-Based Detection of FEN1 Nuclease Activity and Screening of Small-Molecule Inhibitors
05:46

Fluorescence-Based Detection of FEN1 Nuclease Activity and Screening of Small-Molecule Inhibitors

Published on: June 27, 2025

215

A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells

Marium Rana1,2, Alessio Perotti1, Lucy M Bisset1

  • 1School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Metallomics : Integrated Biometal Science
|June 11, 2022
PubMed

Insights

A novel ferronucleoside, 1-(S,Rp), shows potent anti-cancer activity against pancreatic ductal adenocarcinoma (PDAC) cells, including gemcitabine-resistant types. This organometallic compound inhibits DNA replication and induces cell cycle arrest, offering a promising new therapeutic avenue for PDAC.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
  • Existing therapies, such as gemcitabine, often face resistance, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To evaluate the efficacy and mechanism of action of a novel organometallic nucleoside analogue, ferronucleoside 1-(S,Rp), against PDAC cells.
  • To assess the potential of 1-(S,Rp) as a treatment for gemcitabine-resistant PDAC.

Main Methods:

  • Cytotoxicity assays were performed on a panel of PDAC cell lines, including gemcitabine-resistant variants.
  • Mechanistic studies involved DNA-fibre fluorography, cell cycle analysis, and assessment of DNA damage response markers.
  • Transcriptional profiling and Western blotting were used to analyze cellular responses to treatment.

Main Results:

  • Ferronucleoside 1-(S,Rp) demonstrated significant cytotoxicity against PDAC cell lines, with IC50 values comparable to cisplatin.
  • The compound inhibited DNA replication, induced S-phase arrest, and stalled replication forks, as visualized by DNA-fibre fluorography.
  • Treatment led to the activation of DNA damage response pathways, including checkpoint complexes and replication stress markers, partly independent of p53.

Conclusions:

  • Ferronucleoside 1-(S,Rp) exhibits potent anti-cancer activity in PDAC, including gemcitabine-resistant models.
  • Its mechanism involves the inhibition of DNA replication and induction of replication stress.
  • 1-(S,Rp) represents a promising candidate for the development of novel PDAC therapies.
Keywords:
DNA replicationFerrocenenucleoside analoguepancreatic cancerreplication fork arrest

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