Rana, Marium;
Perotti, Alessio;
Bisset, Lucy M;
Smith, James D;
Lamden, Emma;
Khan, Zahra;
Ismail, Media K;
... Hodges, Nikolas J; + view all
(2022)
A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells.
Metallomics
, 14
(7)
, Article mfac041. 10.1093/mtomcs/mfac041.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/mtomcs/mfac041 |
| Publisher version: | https://doi.org/10.1093/mtomcs/mfac041 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2022. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Ferrocene, DNA replication, nucleoside analogue, replication fork arrest, pancreatic cancer, CHK1 INHIBITOR, GEMCITABINE, DERIVATIVES, COMPLEXES, PROTEIN, P53, MECHANISMS, ANTIFUNGAL, LY2603618, INDUCTION |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10154179 |
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