eprintid: 10106639
rev_number: 14
eprint_status: archive
userid: 608
dir: disk0/10/10/66/39
datestamp: 2020-08-07 15:29:05
lastmod: 2021-10-05 00:45:16
status_changed: 2020-08-07 15:29:05
type: article
metadata_visibility: show
creators_name: Ahmed, AA
creators_name: Marchetti, C
creators_name: Ohnmacht, SA
creators_name: Neidle, S
title: A G-quadruplex-binding compound shows potent activity in human gemcitabine-resistant pancreatic cancer cells
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D10
keywords: Cancer, Chemical biology, Drug discovery
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abstract: Gemcitabine is a drug of choice in the treatment of human pancreatic cancer. Chemo-resistance to this drug is common and has been attributed to a variety of distinct mechanisms, involving > 100 genes. A recently developed small-molecule G-quadruplex ligand, the trisubstituted naphthalene diimide compound CM03, has previously been shown to have equivalent potency to gemcitabine in the pancreatic cancer cell line MIA PaCa-2. We report here on cell lines of increased resistance to gemcitabine that have been generated from this line, with the most resistant having 1,000-fold reduced sensitivity to gemcitabine. These resistant lines retain nM sensitivity to CM03. The molecular basis for the retention of potency by this G-quadruplex ligand has been examined using whole transcriptome data analysis with RNA-seq. This has revealed that the pattern of pathways down regulated by CM03 in the parental MIA PaCa-2 cell line is largely unaffected in the gemcitabine-resistant line. The analysis has also shown that the expression patterns of numerous genes involved in gemcitabine sensitivity are down regulated in the resistant line upon CM03 treatment. These results are supportive of the concept that G-quadruplex small molecules such as CM03 have potential for clinical use in the treatment of gemcitabine-resistant human pancreatic cancer.
date: 2020-07-22
date_type: published
official_url: https://doi.org/10.1038/s41598-020-68944-w
oa_status: green
full_text_type: pub
pmcid: PMC7376204
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1800636
doi: 10.1038/s41598-020-68944-w
pii: 10.1038/s41598-020-68944-w
lyricists_name: Neidle, Stephen
lyricists_id: SNEID18
actors_name: Wong, Ian
actors_name: Harris, Jean
actors_id: ICKWO00
actors_id: JAHAR68
actors_role: owner
actors_role: impersonator
full_text_status: public
publication: Scientific Reports
volume: 10
article_number: 12192
event_location: England
citation:        Ahmed, AA;    Marchetti, C;    Ohnmacht, SA;    Neidle, S;      (2020)    A G-quadruplex-binding compound shows potent activity in human gemcitabine-resistant pancreatic cancer cells.                   Scientific Reports , 10     , Article 12192.  10.1038/s41598-020-68944-w <https://doi.org/10.1038/s41598-020-68944-w>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10106639/1/s41598-020-68944-w.pdf