No Cover Image

Journal article 362 views 50 downloads

Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

Nur Aininie Yusoh, Paul Tiley, Steffan James, Siti Norain Harun, Jim A. Thomas Orcid Logo, Norazalina Saad, Ling-Wei Hii, Suet Lin Chia, Martin Gill Orcid Logo, Haslina Ahmad

Journal of Medicinal Chemistry, Volume: 66, Issue: 10, Pages: 6922 - 6937

Swansea University Authors: Paul Tiley, Steffan James, Martin Gill Orcid Logo

  • 63458.pdf

    PDF | Version of Record

    © The Authors, 2023. Published by American Chemical Society. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0).

    Download (8.06MB)

Abstract

Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a “micro-library” comprising a mix of commer...

Full description

Published in: Journal of Medicinal Chemistry
ISSN: 0022-2623 1520-4804
Published: American Chemical Society (ACS) 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa63458
Tags: Add Tag
No Tags, Be the first to tag this record!
Abstract: Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a “micro-library” comprising a mix of commercially available drugs and DNA-binding ruthenium(II) polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficient triple-negative breast cancer cells. This identified three hits: the natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles. All combinations identified were effective in BRCA-proficient breast cancer cells, including an Olaparib-resistant cell line, and spheroid models. Mechanistic studies indicated that synergy was achieved via DNA-damage enhancement and resultant apoptosis. Combinations showed low cytotoxicity toward non-malignant breast epithelial cells and low acute and developmental toxicity in zebrafish embryos. This work identifies RPC metallomacrocycles as a novel class of agents for cancer combination therapy and provides a proof of concept for the inclusion of metallocompounds within drug synergy screens.
Keywords: Cancer, Cells, Dietary supplements, Toxicity, Toxicological synergy
College: Faculty of Science and Engineering
Funders: This work was supported by the Welsh Government and a Sêr Cymru Strategic Partner Acceleration Award 80761-SU-242 as well as the Royal Society of Chemistry (RSC) Research Fund and Research Enablement grants R20-8717 and E21-9540096197.
Issue: 10
Start Page: 6922
End Page: 6937