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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
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URI: https://cronfa.swan.ac.uk/Record/cronfa63458
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spelling v2 63458 2023-05-16 Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy 36246328a726c8861982cd62dee7327b Paul Tiley Paul Tiley true false 4306c32a96e0218af100530cd34d68ee Steffan James Steffan James true false 485d85b532851e8863cd19c6af7e00f7 0000-0002-1371-5676 Martin Gill Martin Gill true false 2023-05-16 CHEM 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. Journal Article Journal of Medicinal Chemistry 66 10 6922 6937 American Chemical Society (ACS) 0022-2623 1520-4804 Cancer, Cells, Dietary supplements, Toxicity, Toxicological synergy 25 5 2023 2023-05-25 10.1021/acs.jmedchem.3c00322 http://dx.doi.org/10.1021/acs.jmedchem.3c00322 COLLEGE NANME Chemistry COLLEGE CODE CHEM Swansea University SU Library paid the OA fee (TA Institutional Deal) 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. 2023-06-21T12:01:23.6055397 2023-05-16T09:29:48.8508390 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Nur Aininie Yusoh 1 Paul Tiley 2 Steffan James 3 Siti Norain Harun 4 Jim A. Thomas 0000-0002-8662-7917 5 Norazalina Saad 6 Ling-Wei Hii 7 Suet Lin Chia 8 Martin Gill 0000-0002-1371-5676 9 Haslina Ahmad 10 63458__27725__199ad70be9be42359e335260320b289f.pdf 63458.pdf 2023-06-06T15:04:50.2622444 Output 8447610 application/pdf Version of Record true © The Authors, 2023. Published by American Chemical Society. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
spellingShingle Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
Paul Tiley
Steffan James
Martin Gill
title_short Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
title_full Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
title_fullStr Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
title_full_unstemmed Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
title_sort Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
author_id_str_mv 36246328a726c8861982cd62dee7327b
4306c32a96e0218af100530cd34d68ee
485d85b532851e8863cd19c6af7e00f7
author_id_fullname_str_mv 36246328a726c8861982cd62dee7327b_***_Paul Tiley
4306c32a96e0218af100530cd34d68ee_***_Steffan James
485d85b532851e8863cd19c6af7e00f7_***_Martin Gill
author Paul Tiley
Steffan James
Martin Gill
author2 Nur Aininie Yusoh
Paul Tiley
Steffan James
Siti Norain Harun
Jim A. Thomas
Norazalina Saad
Ling-Wei Hii
Suet Lin Chia
Martin Gill
Haslina Ahmad
format Journal article
container_title Journal of Medicinal Chemistry
container_volume 66
container_issue 10
container_start_page 6922
publishDate 2023
institution Swansea University
issn 0022-2623
1520-4804
doi_str_mv 10.1021/acs.jmedchem.3c00322
publisher American Chemical Society (ACS)
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
url http://dx.doi.org/10.1021/acs.jmedchem.3c00322
document_store_str 1
active_str 0
description 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.
published_date 2023-05-25T12:01:22Z
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