A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells.
DNA replication
Ferrocene
nucleoside analogue
pancreatic cancer
replication fork arrest
Journal
Metallomics : integrated biometal science
ISSN: 1756-591X
Titre abrégé: Metallomics
Pays: England
ID NLM: 101478346
Informations de publication
Date de publication:
25 07 2022
25 07 2022
Historique:
received:
20
04
2022
accepted:
11
05
2022
pubmed:
12
6
2022
medline:
28
7
2022
entrez:
11
6
2022
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.
Identifiants
pubmed: 35689667
pii: 6605925
doi: 10.1093/mtomcs/mfac041
pmc: PMC9320222
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
DNA-Binding Proteins
0
Metallocenes
0
Nucleosides
0
Rad17 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Cancer Research UK
ID : 20147
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206343/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
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