Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth
A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and p...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-12, Vol.105 (50), p.19579-19586 |
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container_title | Proceedings of the National Academy of Sciences - PNAS |
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creator | Zhang, Huafeng Qian, David Z Tan, Yee Sun Lee, KangAe Gao, Ping Ren, Yunzhao R Rey, Sergio Hammers, Hans Chang, Daniel Pili, Roberto Dang, Chi V Liu, Jun O Semenza, Gregg L |
description | A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1α protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1α by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy. |
doi_str_mv | 10.1073/pnas.0809763105 |
format | Article |
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Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1α protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1α by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0809763105</identifier><identifier>PMID: 19020076</identifier><language>eng</language><publisher>National Academy of Sciences</publisher><subject>Biological Sciences ; Cancer ; Cardiac glycosides ; Cell growth ; Cultured cells ; Heterologous transplantation ; Hypoxia ; Messenger RNA ; Protein synthesis ; Tumors ; Vehicles</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-12, Vol.105 (50), p.19579-19586</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>2008 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-64cc58dbb079f8c720b4151fb4a72b601e1b78471738a3ca2a185d82764683163</citedby><cites>FETCH-LOGICAL-c442t-64cc58dbb079f8c720b4151fb4a72b601e1b78471738a3ca2a185d82764683163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/50.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25465691$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25465691$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids></links><search><creatorcontrib>Zhang, Huafeng</creatorcontrib><creatorcontrib>Qian, David Z</creatorcontrib><creatorcontrib>Tan, Yee Sun</creatorcontrib><creatorcontrib>Lee, KangAe</creatorcontrib><creatorcontrib>Gao, Ping</creatorcontrib><creatorcontrib>Ren, Yunzhao R</creatorcontrib><creatorcontrib>Rey, Sergio</creatorcontrib><creatorcontrib>Hammers, Hans</creatorcontrib><creatorcontrib>Chang, Daniel</creatorcontrib><creatorcontrib>Pili, Roberto</creatorcontrib><creatorcontrib>Dang, Chi V</creatorcontrib><creatorcontrib>Liu, Jun O</creatorcontrib><creatorcontrib>Semenza, Gregg L</creatorcontrib><title>Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth</title><title>Proceedings of the National Academy of Sciences - PNAS</title><description>A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). 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Enforced expression of HIF-1α by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy.</description><subject>Biological Sciences</subject><subject>Cancer</subject><subject>Cardiac glycosides</subject><subject>Cell growth</subject><subject>Cultured cells</subject><subject>Heterologous transplantation</subject><subject>Hypoxia</subject><subject>Messenger RNA</subject><subject>Protein synthesis</subject><subject>Tumors</subject><subject>Vehicles</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNqFkL1uFDEUhS1ERJZATYVwm2KSez3-bZBQQkikSClga8v2_KzD7Hhlz0L2sXgRnolZNkpEReXi-8651iHkHcIZgqrPN6MrZ6DBKFkjiBdkgWCwktzAS7IAYKrSnPFj8rqUewAwQsMrcowGGICSC7K8jH16iCN1Y0PTtGozDS430QXaD7uQSmzaQuO4ij5O9PrmqsLfv2jZjbNaYvkb80MK3-m0XadM-5x-Tqs35KhzQ2nfPr4nZHn1-dvFdXV79-Xm4tNtFThn0_zNEIRuvAdlOh0UA89RYOe5U8xLwBa90lyhqrWrg2MOtWg0U5JLXaOsT8jHQ-9m69dtE9pxym6wmxzXLu9sctH-S8a4sn36YZkEbriYC84PBSGnUnLbPWUR7H5hu1_YPi88J04fT-7Bsy2smBNGKGO77TBM7cM0u_Q_7qy8Pyj3ZUr5yWGCSyENzvzDgXcuWdfnWOzyKwOsAYVCDbz-A-T_miU</recordid><startdate>20081216</startdate><enddate>20081216</enddate><creator>Zhang, Huafeng</creator><creator>Qian, David Z</creator><creator>Tan, Yee Sun</creator><creator>Lee, KangAe</creator><creator>Gao, Ping</creator><creator>Ren, Yunzhao R</creator><creator>Rey, Sergio</creator><creator>Hammers, Hans</creator><creator>Chang, Daniel</creator><creator>Pili, Roberto</creator><creator>Dang, Chi V</creator><creator>Liu, Jun O</creator><creator>Semenza, Gregg L</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20081216</creationdate><title>Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth</title><author>Zhang, Huafeng ; Qian, David Z ; Tan, Yee Sun ; Lee, KangAe ; Gao, Ping ; Ren, Yunzhao R ; Rey, Sergio ; Hammers, Hans ; Chang, Daniel ; Pili, Roberto ; Dang, Chi V ; Liu, Jun O ; Semenza, Gregg L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-64cc58dbb079f8c720b4151fb4a72b601e1b78471738a3ca2a185d82764683163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Biological Sciences</topic><topic>Cancer</topic><topic>Cardiac glycosides</topic><topic>Cell growth</topic><topic>Cultured cells</topic><topic>Heterologous transplantation</topic><topic>Hypoxia</topic><topic>Messenger RNA</topic><topic>Protein synthesis</topic><topic>Tumors</topic><topic>Vehicles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Huafeng</creatorcontrib><creatorcontrib>Qian, David Z</creatorcontrib><creatorcontrib>Tan, Yee Sun</creatorcontrib><creatorcontrib>Lee, KangAe</creatorcontrib><creatorcontrib>Gao, Ping</creatorcontrib><creatorcontrib>Ren, Yunzhao R</creatorcontrib><creatorcontrib>Rey, Sergio</creatorcontrib><creatorcontrib>Hammers, Hans</creatorcontrib><creatorcontrib>Chang, Daniel</creatorcontrib><creatorcontrib>Pili, Roberto</creatorcontrib><creatorcontrib>Dang, Chi V</creatorcontrib><creatorcontrib>Liu, Jun O</creatorcontrib><creatorcontrib>Semenza, Gregg L</creatorcontrib><collection>AGRIS</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Huafeng</au><au>Qian, David Z</au><au>Tan, Yee Sun</au><au>Lee, KangAe</au><au>Gao, Ping</au><au>Ren, Yunzhao R</au><au>Rey, Sergio</au><au>Hammers, Hans</au><au>Chang, Daniel</au><au>Pili, Roberto</au><au>Dang, Chi V</au><au>Liu, Jun O</au><au>Semenza, Gregg L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><date>2008-12-16</date><risdate>2008</risdate><volume>105</volume><issue>50</issue><spage>19579</spage><epage>19586</epage><pages>19579-19586</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 μM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1α protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1α by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy.</abstract><pub>National Academy of Sciences</pub><pmid>19020076</pmid><doi>10.1073/pnas.0809763105</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biological Sciences Cancer Cardiac glycosides Cell growth Cultured cells Heterologous transplantation Hypoxia Messenger RNA Protein synthesis Tumors Vehicles |
title | Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth |
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