Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines
Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While in...
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| description | Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES. |
| doi_str_mv | 10.1371/journal.pone.0222228 |
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The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0222228</identifier><identifier>PMID: 31550266</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject><![CDATA[Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - therapeutic use ; Biotechnology ; Bone cancer ; Bone Neoplasms - drug therapy ; Bone Neoplasms - enzymology ; Cancer therapies ; Cell cycle ; Cell Line, Tumor ; Chemotherapy ; Clinical trials ; Cyclophosphamide ; Cyclophosphamide - administration & dosage ; Cyclophosphamide - therapeutic use ; Depsipeptides - administration & dosage ; Depsipeptides - therapeutic use ; Doxorubicin ; Doxorubicin - administration & dosage ; Doxorubicin - therapeutic use ; Drug Synergism ; Drug Therapy, Combination - methods ; Epigenetics ; Etoposide ; Etoposide - administration & dosage ; Etoposide - therapeutic use ; Ewing's sarcoma ; Ewings sarcoma ; Experimentation ; FLI-1 protein ; Histone deacetylase ; Histone Deacetylase Inhibitors - administration & dosage ; Histone Deacetylase Inhibitors - therapeutic use ; Histone Deacetylases - drug effects ; Histone Deacetylases - metabolism ; Histone Demethylases - antagonists & inhibitors ; Histones ; Humans ; Hydrazines - administration & dosage ; Hydrazines - therapeutic use ; Inhibitors ; Irinotecan ; Irinotecan - administration & dosage ; Irinotecan - therapeutic use ; Lysine ; Medical research ; Medicine and Health Sciences ; Metabolites ; NuRD protein ; Pediatrics ; Prostate cancer ; Reagents ; Research and Analysis Methods ; Sarcoma ; Sarcoma, Ewing - drug therapy ; Sarcoma, Ewing - enzymology ; Sulfonamides - administration & dosage ; Sulfonamides - therapeutic use ; Teenagers ; Transcription factors ; Translocation ; Tumor cell lines ; Vincristine ; Vincristine - administration & dosage ; Vincristine - therapeutic use ; Young adults]]></subject><ispartof>PloS one, 2019-09, Vol.14 (9), p.e0222228</ispartof><rights>2019 Welch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. 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methods</subject><subject>Epigenetics</subject><subject>Etoposide</subject><subject>Etoposide - administration & dosage</subject><subject>Etoposide - therapeutic use</subject><subject>Ewing's sarcoma</subject><subject>Ewings sarcoma</subject><subject>Experimentation</subject><subject>FLI-1 protein</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - administration & dosage</subject><subject>Histone Deacetylase Inhibitors - therapeutic use</subject><subject>Histone Deacetylases - drug effects</subject><subject>Histone Deacetylases - metabolism</subject><subject>Histone Demethylases - antagonists & inhibitors</subject><subject>Histones</subject><subject>Humans</subject><subject>Hydrazines - administration & dosage</subject><subject>Hydrazines - therapeutic use</subject><subject>Inhibitors</subject><subject>Irinotecan</subject><subject>Irinotecan - administration & dosage</subject><subject>Irinotecan - therapeutic use</subject><subject>Lysine</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Metabolites</subject><subject>NuRD protein</subject><subject>Pediatrics</subject><subject>Prostate cancer</subject><subject>Reagents</subject><subject>Research and Analysis Methods</subject><subject>Sarcoma</subject><subject>Sarcoma, Ewing - drug therapy</subject><subject>Sarcoma, Ewing - enzymology</subject><subject>Sulfonamides - administration & dosage</subject><subject>Sulfonamides - therapeutic use</subject><subject>Teenagers</subject><subject>Transcription factors</subject><subject>Translocation</subject><subject>Tumor cell lines</subject><subject>Vincristine</subject><subject>Vincristine - administration & dosage</subject><subject>Vincristine - therapeutic use</subject><subject>Young adults</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1UstuGyEURVWrJnH7B1WL1E26GBcG89pEipy0iWSpi2SPGIaxsRhwYdzKH9L_DRNPomRRNjzuOecerg4AnzCaY8Lx923cp6D9fBeDnaN6XOINOMWS1BWrEXn74nwCznLeIkSJYOw9OCGYUlQzdgr-3fXae9hHb83eW-jCxjVucDHA2EF_yC7YKu-scZ0zsLW9HTYHr7OFGJ6v7q7wN6hDCzcuD8VHAWhjhyPg_ObqclnKfiyMIBegiX3jgn7UL9frvy6sYdapvGtobHHiS8P8AbzrtM_247TPwP2P6_vlTbX69fN2ebmqDOV8qCTDnDDZWMMYbSUzNeaMLLSgaNHItpaMC45R-WlHa8FapFuqjaSc8oVgDZmBL0fZnY9ZTQPNqi7EIkPK-Gbg9ohoo96qXXK9TgcVtVOPDzGtlU6DM94qQ5rGSC4kwd2CdEJgiyS20rSiDJ2KonUxdds3vW2NDUPS_pXo60pwG7WOfxTjVGLGi8DXSSDF33ubh_9YXhxRJsWck-2eO2CkxuQ8sdSYHDUlp9A-v3T3THqKCnkANMjBKA</recordid><startdate>20190924</startdate><enddate>20190924</enddate><creator>Welch, Darcy</creator><creator>Kahen, Elliot</creator><creator>Fridley, Brooke</creator><creator>Brohl, Andrew S</creator><creator>Cubitt, Christopher L</creator><creator>Reed, Damon R</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8238-2465</orcidid><orcidid>https://orcid.org/0000-0003-2753-6684</orcidid></search><sort><creationdate>20190924</creationdate><title>Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines</title><author>Welch, Darcy ; Kahen, Elliot ; Fridley, Brooke ; Brohl, Andrew S ; Cubitt, Christopher L ; Reed, Damon R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c577t-9617369bec665d96c217634a8504b9d29678710026f5286d0ad5ac95757486b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Antineoplastic Agents - 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The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31550266</pmid><doi>10.1371/journal.pone.0222228</doi><orcidid>https://orcid.org/0000-0002-8238-2465</orcidid><orcidid>https://orcid.org/0000-0003-2753-6684</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2296634319 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Antineoplastic Agents - administration & dosage Antineoplastic Agents - therapeutic use Biotechnology Bone cancer Bone Neoplasms - drug therapy Bone Neoplasms - enzymology Cancer therapies Cell cycle Cell Line, Tumor Chemotherapy Clinical trials Cyclophosphamide Cyclophosphamide - administration & dosage Cyclophosphamide - therapeutic use Depsipeptides - administration & dosage Depsipeptides - therapeutic use Doxorubicin Doxorubicin - administration & dosage Doxorubicin - therapeutic use Drug Synergism Drug Therapy, Combination - methods Epigenetics Etoposide Etoposide - administration & dosage Etoposide - therapeutic use Ewing's sarcoma Ewings sarcoma Experimentation FLI-1 protein Histone deacetylase Histone Deacetylase Inhibitors - administration & dosage Histone Deacetylase Inhibitors - therapeutic use Histone Deacetylases - drug effects Histone Deacetylases - metabolism Histone Demethylases - antagonists & inhibitors Histones Humans Hydrazines - administration & dosage Hydrazines - therapeutic use Inhibitors Irinotecan Irinotecan - administration & dosage Irinotecan - therapeutic use Lysine Medical research Medicine and Health Sciences Metabolites NuRD protein Pediatrics Prostate cancer Reagents Research and Analysis Methods Sarcoma Sarcoma, Ewing - drug therapy Sarcoma, Ewing - enzymology Sulfonamides - administration & dosage Sulfonamides - therapeutic use Teenagers Transcription factors Translocation Tumor cell lines Vincristine Vincristine - administration & dosage Vincristine - therapeutic use Young adults |
| title | Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T17%3A49%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Small%20molecule%20inhibition%20of%20lysine-specific%20demethylase%201%20(LSD1)%20and%20histone%20deacetylase%20(HDAC)%20alone%20and%20in%20combination%20in%20Ewing%20sarcoma%20cell%20lines&rft.jtitle=PloS%20one&rft.au=Welch,%20Darcy&rft.date=2019-09-24&rft.volume=14&rft.issue=9&rft.spage=e0222228&rft.pages=e0222228-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0222228&rft_dat=%3Cproquest_plos_%3E2296634319%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2296634319&rft_id=info:pmid/31550266&rft_doaj_id=oai_doaj_org_article_c3bbc978931f43f881e091e9cd886658&rfr_iscdi=true |