eprintid: 10117135
rev_number: 14
eprint_status: archive
userid: 608
dir: disk0/10/11/71/35
datestamp: 2020-12-14 11:25:26
lastmod: 2021-10-09 22:31:26
status_changed: 2020-12-14 11:25:26
type: article
metadata_visibility: show
creators_name: Ahmed, AA
creators_name: Neidle, S
title: A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D10
keywords: CM03, drug synergy, gemcitabine resistance, histone deacetylase (HDAC) inhibitor vorinostat, naphthalene diimide derivative, pancreatic cancer, quadruplex
note: © 2020 by the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
abstract: The stabilisation of G-quadruplexes (G4s) by small-molecule compounds is an effective approach for causing cell growth arrest, followed by cell death. Some of these compounds are currently being developed for the treatment of human cancers. We have previously developed a substituted naphthalene diimide G4-binding molecule (CM03) with selective potency for pancreatic cancer cells, including gemcitabine-resistant cells. We report here that CM03 and the histone deacetylase (HDAC) inhibitor SAHA (suberanilohydroxamic acid) have synergistic effects at concentrations close to and below their individual GI_{50} values, in both gemcitabine-sensitive and resistant pancreatic cancer cell lines. Immunoblot analysis showed elevated levels of γ-H2AX and cleaved PARP proteins upon drug combination treatment, indicating increased levels of DNA damage (double-strand break events: DSBs) and apoptosis induction, respectively. We propose that the mechanism of synergy involves SAHA relaxing condensed chromatin, resulting in higher levels of G4 formation. In turn, CM03 can stabilise a greater number of G4s, leading to the downregulation of more G4-containing genes as well as a higher incidence of DSBs due to torsional strain on DNA and chromatin structure.
date: 2020-11-02
date_type: published
official_url: https://doi.org/10.3390/molecules25225407
oa_status: green
full_text_type: pub
pmcid: PMC7699281
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1832683
doi: 10.3390/molecules25225407
pii: molecules25225407
lyricists_name: Neidle, Stephen
lyricists_id: SNEID18
actors_name: Neidle, Stephen
actors_name: Harris, Jean
actors_id: SNEID18
actors_id: JAHAR68
actors_role: owner
actors_role: impersonator
full_text_status: public
publication: Molecules
volume: 25
number: 22
article_number: 5407
event_location: Switzerland
citation:        Ahmed, AA;    Neidle, S;      (2020)    A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells.                   Molecules , 25  (22)    , Article 5407.  10.3390/molecules25225407 <https://doi.org/10.3390/molecules25225407>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10117135/1/molecules-25-05407-v2.pdf