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 comme...
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| Veröffentlicht in: | Journal of medicinal chemistry 2023-05, Vol.66 (10), p.6922-6937 |
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| creator | Yusoh, Nur Aininie Tiley, Paul R. James, Steffan D. Harun, Siti Norain Thomas, Jim A. Saad, Norazalina Hii, Ling-Wei Chia, Suet Lin Gill, Martin R. Ahmad, Haslina |
| 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. |
| doi_str_mv | 10.1021/acs.jmedchem.3c00322 |
| format | Article |
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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c00322</identifier><identifier>PMID: 37185020</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Cell Line, Tumor ; DNA ; Female ; Humans ; Ovarian Neoplasms - drug therapy ; Phthalazines - pharmacology ; Phthalazines - therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use ; Ruthenium - pharmacology ; Ruthenium - therapeutic use ; Zebrafish</subject><ispartof>Journal of medicinal chemistry, 2023-05, Vol.66 (10), p.6922-6937</ispartof><rights>2023 The Authors. 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Med. Chem</addtitle><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.</description><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>DNA</subject><subject>Female</subject><subject>Humans</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Phthalazines - pharmacology</subject><subject>Phthalazines - therapeutic use</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use</subject><subject>Ruthenium - pharmacology</subject><subject>Ruthenium - therapeutic use</subject><subject>Zebrafish</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS1ERbeFb4BQjuWQ7fhPEueE0BbKSkWVoFyxJrbTTZXYwU4q5dvjstuKXnqw5uDfezN6j5D3FNYUGD1HHdd3gzV6Z4c11wCcsVdkRQsGuZAgXpMVAGM5Kxk_Jicx3kFiKONvyDGvqCyAwYr8vuii9vc2LJlvsx_ztLOum4ez7fZj9t1O2Pde-2H0szMZpnfd44iha7Kfi7PhdslaH7INOm3T8EPTOZw677KbnQ04Lm_JUYt9tO8O85T8-vrlZvMtv7q-3G4-X-UoCphyKS3ooqrrtqlMZY1p66ZmUJRlKVvBq4ZDrQ2KtqbMCDRYl1K3RnM0gI2V_JR82vuOc_OQiXVTwF6NoRswLMpjp57_uG6nbv29SlGyEgRNDmcHh-D_zDZOakjJ2L5HZ_0cFZNUFIzLskqo2KM6-BiDbZ_2UHgwpCp1ox67UYdukuzD_zc-iR7LSADsgX9yPweXInvZ8y-hnKDO</recordid><startdate>20230525</startdate><enddate>20230525</enddate><creator>Yusoh, Nur Aininie</creator><creator>Tiley, Paul R.</creator><creator>James, Steffan D.</creator><creator>Harun, Siti Norain</creator><creator>Thomas, Jim A.</creator><creator>Saad, Norazalina</creator><creator>Hii, Ling-Wei</creator><creator>Chia, Suet Lin</creator><creator>Gill, Martin R.</creator><creator>Ahmad, Haslina</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1371-5676</orcidid><orcidid>https://orcid.org/0000-0002-8662-7917</orcidid></search><sort><creationdate>20230525</creationdate><title>Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy</title><author>Yusoh, Nur Aininie ; 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| ispartof | Journal of medicinal chemistry, 2023-05, Vol.66 (10), p.6922-6937 |
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| subjects | Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Cell Line, Tumor DNA Female Humans Ovarian Neoplasms - drug therapy Phthalazines - pharmacology Phthalazines - therapeutic use Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Ruthenium - pharmacology Ruthenium - therapeutic use Zebrafish |
| title | Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy |
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