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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

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DOI (Published version): 10.1021/acs.jmedchem.3c00322

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...

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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
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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

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