Discovery of ruthenium(ii) metallocompound and olaparib synergy for cancer combination therapy
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Chemical Society
2023
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| Online Access: | http://psasir.upm.edu.my/id/eprint/107358/ http://psasir.upm.edu.my/id/eprint/107358/1/107358.pdf |
| _version_ | 1848864877021495296 |
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| author | Yusoh, Nur Aininie Tiley, Paul R. James, Steffan D. Harun, Siti Norain Thomas, Jim A. Saad, Norazalina Ling, Wei Hii Suet, Lin Chia Gill, Martin R. Ahmad, Haslina |
| author_facet | Yusoh, Nur Aininie Tiley, Paul R. James, Steffan D. Harun, Siti Norain Thomas, Jim A. Saad, Norazalina Ling, Wei Hii Suet, Lin Chia Gill, Martin R. Ahmad, Haslina |
| author_sort | Yusoh, Nur Aininie |
| building | UPM Institutional Repository |
| collection | Online Access |
| 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. |
| first_indexed | 2025-11-15T13:55:47Z |
| format | Article |
| id | upm-107358 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T13:55:47Z |
| publishDate | 2023 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-1073582024-11-04T04:04:30Z http://psasir.upm.edu.my/id/eprint/107358/ Discovery of ruthenium(ii) metallocompound and olaparib synergy for cancer combination therapy Yusoh, Nur Aininie Tiley, Paul R. James, Steffan D. Harun, Siti Norain Thomas, Jim A. Saad, Norazalina Ling, Wei Hii Suet, Lin Chia Gill, Martin R. Ahmad, Haslina 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. American Chemical Society 2023-05-15 Article PeerReviewed text en cc_by_4 http://psasir.upm.edu.my/id/eprint/107358/1/107358.pdf Yusoh, Nur Aininie and Tiley, Paul R. and James, Steffan D. and Harun, Siti Norain and Thomas, Jim A. and Saad, Norazalina and Ling, Wei Hii and Suet, Lin Chia and Gill, Martin R. and Ahmad, Haslina (2023) Discovery of ruthenium(ii) metallocompound and olaparib synergy for cancer combination therapy. Journal of Medicinal Chemistry, 66 (10). 6922 - 6937. ISSN 0022-2623; eISSN: 1520-4804 https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00322 10.1021/acs.jmedchem.3c00322 |
| spellingShingle | Yusoh, Nur Aininie Tiley, Paul R. James, Steffan D. Harun, Siti Norain Thomas, Jim A. Saad, Norazalina Ling, Wei Hii Suet, Lin Chia Gill, Martin R. Ahmad, Haslina Discovery of ruthenium(ii) metallocompound and olaparib synergy for cancer combination therapy |
| title | 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_short | 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 |
| url | http://psasir.upm.edu.my/id/eprint/107358/ http://psasir.upm.edu.my/id/eprint/107358/ http://psasir.upm.edu.my/id/eprint/107358/ http://psasir.upm.edu.my/id/eprint/107358/1/107358.pdf |