Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents
Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pat...
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| description | Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+)/K(+)-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members--digitoxin and digoxin--down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+) ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs. |
| doi_str_mv | 10.1371/journal.pone.0075905 |
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DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+)/K(+)-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members--digitoxin and digoxin--down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+) ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0075905</identifier><identifier>PMID: 24124520</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anemia ; Anticancer properties ; Antineoplastic agents ; Antineoplastic drugs ; Antitumor agents ; Apoptosis ; Blotting, Western ; Calcium ; Calcium ions ; Cancer therapies ; Cancer treatment ; Cardiovascular diseases ; Cell cycle ; Cell Cycle - drug effects ; Cell Line, Tumor ; Cell Survival - drug effects ; Chemosensitization ; Chemotherapy ; Cisplatin ; Cisplatin - pharmacology ; Colorectal cancer ; Coronary artery disease ; Crosslinking ; Cytotoxicity ; Deoxyribonucleic acid ; Digoxin ; DNA ; DNA damage ; DNA repair ; Drug development ; Drug resistance ; Drugs ; Enzymes ; Fanconi Anemia - metabolism ; Fanconi syndrome ; Fanconi's anemia ; Fluorescent Antibody Technique ; Gene expression ; Glycosides ; Heart ; Heart diseases ; Humans ; Inhibition ; Kinases ; Lesions ; MAP kinase ; Medical screening ; Mitomycin - pharmacology ; Mitomycin C ; Molecular biology ; Molecular chains ; mRNA ; Multiple myeloma ; Na+/K+-exchanging ATPase ; Ouabain ; Ouabain - pharmacology ; Prostate ; Proteins ; Repair ; RNA ; Signal transduction ; Signal Transduction - drug effects ; Sodium-Potassium-Exchanging ATPase - metabolism ; Tumor cells ; Ubiquitination</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e75905</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Jun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Jun et al 2013 Jun et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-8fa135856dac0b65112a73a8d895cfef6af4017abfafa89cfc86e1967a1781583</citedby><cites>FETCH-LOGICAL-c758t-8fa135856dac0b65112a73a8d895cfef6af4017abfafa89cfc86e1967a1781583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790830/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790830/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23855,27913,27914,53780,53782,79359,79360</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24124520$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Fei, Peiwen</contributor><creatorcontrib>Jun, Dong Wha</creatorcontrib><creatorcontrib>Hwang, Mihwa</creatorcontrib><creatorcontrib>Kim, Hyun Jung</creatorcontrib><creatorcontrib>Hwang, Soo Kyung</creatorcontrib><creatorcontrib>Kim, Sunshin</creatorcontrib><creatorcontrib>Lee, Chang-Hun</creatorcontrib><title>Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+)/K(+)-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members--digitoxin and digoxin--down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+) ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.</description><subject>Anemia</subject><subject>Anticancer properties</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic drugs</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Blotting, Western</subject><subject>Calcium</subject><subject>Calcium ions</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Cardiovascular diseases</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chemosensitization</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Cisplatin - pharmacology</subject><subject>Colorectal cancer</subject><subject>Coronary artery disease</subject><subject>Crosslinking</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>Digoxin</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Fanconi Anemia - metabolism</subject><subject>Fanconi syndrome</subject><subject>Fanconi's anemia</subject><subject>Fluorescent Antibody Technique</subject><subject>Gene expression</subject><subject>Glycosides</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Kinases</subject><subject>Lesions</subject><subject>MAP kinase</subject><subject>Medical screening</subject><subject>Mitomycin - pharmacology</subject><subject>Mitomycin C</subject><subject>Molecular biology</subject><subject>Molecular chains</subject><subject>mRNA</subject><subject>Multiple myeloma</subject><subject>Na+/K+-exchanging ATPase</subject><subject>Ouabain</subject><subject>Ouabain - pharmacology</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Repair</subject><subject>RNA</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Sodium-Potassium-Exchanging ATPase - metabolism</subject><subject>Tumor cells</subject><subject>Ubiquitination</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</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>eNqNkl1v0zAYhSMEYmPwDxBYQkJCWjs7H7ZzM6kMBpUmKo2PW-uN7aQuqV1iZ6z_HnfNpkYCCeUi0ZvnHNvHJ0leEjwlGSNnK9d3Ftrpxlk9xZgVJS4eJcekzNIJTXH2-OD7KHnm_QrjIuOUPk2O0pykeZHi4-R20UMFxp4iQBI6ZUCipt1K543Sp8jYpalM8CgsNboEK501CKxeGzh7f30xQxsIy9-wRSCDuYGgFaq26MOXWVQG3fnQgVVIds77SWvsT2MbBI22wT9PntTQev1ieJ8k3y8_frv4PLlafJpfzK4mkhU8THgNJCt4QRVIXNGCkBRYBlzxspC1rinUOSYMqhpq4KWsJaealJQBYZwUPDtJXu99N63zYgjNixgKS7Oc8R0x3xPKwUpsOrOGbiscGHE3cF0joAtGtloQWTEMtKaKVzktGGBNleSMlJhCSlT0Oh9W66u1VjKetIN2ZDr-Y81SNO5GZKzEPMPR4M1g0LlfvfbhH1seqAbiroytXTSTa-OlmEUgTwueZpGa_oWKj4r3F29S1ybOR4J3I0Fkgr4NDfTei_nX6_9nFz_G7NsDdqmhDUvv2j4YZ_0YzPfgXWM6XT8kR7DYtf4-DbFrvRhaH2WvDlN_EN3XPPsDFLf9aw</recordid><startdate>20131004</startdate><enddate>20131004</enddate><creator>Jun, Dong Wha</creator><creator>Hwang, Mihwa</creator><creator>Kim, Hyun Jung</creator><creator>Hwang, Soo Kyung</creator><creator>Kim, Sunshin</creator><creator>Lee, Chang-Hun</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>IOV</scope><scope>ISR</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131004</creationdate><title>Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents</title><author>Jun, Dong Wha ; Hwang, Mihwa ; Kim, Hyun Jung ; Hwang, Soo Kyung ; Kim, Sunshin ; Lee, Chang-Hun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-8fa135856dac0b65112a73a8d895cfef6af4017abfafa89cfc86e1967a1781583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Anemia</topic><topic>Anticancer properties</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic drugs</topic><topic>Antitumor agents</topic><topic>Apoptosis</topic><topic>Blotting, Western</topic><topic>Calcium</topic><topic>Calcium ions</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>Cardiovascular diseases</topic><topic>Cell cycle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chemosensitization</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Cisplatin - pharmacology</topic><topic>Colorectal cancer</topic><topic>Coronary artery disease</topic><topic>Crosslinking</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>Digoxin</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Drug development</topic><topic>Drug resistance</topic><topic>Drugs</topic><topic>Enzymes</topic><topic>Fanconi Anemia - metabolism</topic><topic>Fanconi syndrome</topic><topic>Fanconi's anemia</topic><topic>Fluorescent Antibody Technique</topic><topic>Gene expression</topic><topic>Glycosides</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Kinases</topic><topic>Lesions</topic><topic>MAP kinase</topic><topic>Medical screening</topic><topic>Mitomycin - pharmacology</topic><topic>Mitomycin C</topic><topic>Molecular biology</topic><topic>Molecular chains</topic><topic>mRNA</topic><topic>Multiple myeloma</topic><topic>Na+/K+-exchanging ATPase</topic><topic>Ouabain</topic><topic>Ouabain - 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DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+)/K(+)-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members--digitoxin and digoxin--down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+) ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24124520</pmid><doi>10.1371/journal.pone.0075905</doi><tpages>e75905</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2037234788 |
| 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 | Anemia Anticancer properties Antineoplastic agents Antineoplastic drugs Antitumor agents Apoptosis Blotting, Western Calcium Calcium ions Cancer therapies Cancer treatment Cardiovascular diseases Cell cycle Cell Cycle - drug effects Cell Line, Tumor Cell Survival - drug effects Chemosensitization Chemotherapy Cisplatin Cisplatin - pharmacology Colorectal cancer Coronary artery disease Crosslinking Cytotoxicity Deoxyribonucleic acid Digoxin DNA DNA damage DNA repair Drug development Drug resistance Drugs Enzymes Fanconi Anemia - metabolism Fanconi syndrome Fanconi's anemia Fluorescent Antibody Technique Gene expression Glycosides Heart Heart diseases Humans Inhibition Kinases Lesions MAP kinase Medical screening Mitomycin - pharmacology Mitomycin C Molecular biology Molecular chains mRNA Multiple myeloma Na+/K+-exchanging ATPase Ouabain Ouabain - pharmacology Prostate Proteins Repair RNA Signal transduction Signal Transduction - drug effects Sodium-Potassium-Exchanging ATPase - metabolism Tumor cells Ubiquitination |
| title | Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T09%3A51%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ouabain,%20a%20cardiac%20glycoside,%20inhibits%20the%20Fanconi%20anemia/BRCA%20pathway%20activated%20by%20DNA%20interstrand%20cross-linking%20agents&rft.jtitle=PloS%20one&rft.au=Jun,%20Dong%20Wha&rft.date=2013-10-04&rft.volume=8&rft.issue=10&rft.spage=e75905&rft.pages=e75905-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0075905&rft_dat=%3Cgale_plos_%3EA478425823%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2037234788&rft_id=info:pmid/24124520&rft_galeid=A478425823&rft_doaj_id=oai_doaj_org_article_1cb70a6f6d8b4657a0e6dc871906a21d&rfr_iscdi=true |