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Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells

Nur Aininie Yusoh, Suet Lin Chia, Norazalina Saad, Haslina Ahmad, Martin Gill Orcid Logo

Scientific Reports, Volume: 13, Issue: 1

Swansea University Author: Martin Gill Orcid Logo

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DOI (Published version): 10.1038/s41598-023-28454-x

Abstract

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to...

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Published in: Scientific Reports
ISSN: 2045-2322
Published: Springer Science and Business Media LLC 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa62457
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Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz&#x2009;=&#x2009;dipyrido[3,2-a:2&#x2032;,3&#x2032;-c]phenazine, PIP&#x2009;=&#x2009;2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), &#x201C;Ru-PIP&#x201D;, with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. 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spelling 2023-02-10T14:13:39.9244443 v2 62457 2023-01-27 Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells 485d85b532851e8863cd19c6af7e00f7 0000-0002-1371-5676 Martin Gill Martin Gill true false 2023-01-27 CHEM Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), “Ru-PIP”, with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP. Journal Article Scientific Reports 13 1 Springer Science and Business Media LLC 2045-2322 26 1 2023 2023-01-26 10.1038/s41598-023-28454-x COLLEGE NANME Chemistry COLLEGE CODE CHEM Swansea University SU College/Department paid the OA fee This work was supported by the Welsh Government and a Sêr Cymru Strategic Partner Acceleration Award 80761-SU-242 as well as Royal Society of Chemistry (RSC) Research Fund and Research Enablement grants R20-8717 and E21-9540096197. 2023-02-10T14:13:39.9244443 2023-01-27T08:08:06.1329479 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Nur Aininie Yusoh 1 Suet Lin Chia 2 Norazalina Saad 3 Haslina Ahmad 4 Martin Gill 0000-0002-1371-5676 5 62457__26471__6d615149c58e4ff39d66f35eb94d8e61.pdf 62457.pdf 2023-02-06T08:39:58.0589800 Output 5927693 application/pdf Version of Record true © The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
spellingShingle Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
Martin Gill
title_short Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
title_full Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
title_fullStr Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
title_full_unstemmed Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
title_sort Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
author_id_str_mv 485d85b532851e8863cd19c6af7e00f7
author_id_fullname_str_mv 485d85b532851e8863cd19c6af7e00f7_***_Martin Gill
author Martin Gill
author2 Nur Aininie Yusoh
Suet Lin Chia
Norazalina Saad
Haslina Ahmad
Martin Gill
format Journal article
container_title Scientific Reports
container_volume 13
container_issue 1
publishDate 2023
institution Swansea University
issn 2045-2322
doi_str_mv 10.1038/s41598-023-28454-x
publisher Springer Science and Business Media LLC
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
document_store_str 1
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description Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), “Ru-PIP”, with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP.
published_date 2023-01-26T04:22:05Z
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