Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate
Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native...
Gespeichert in:
Veröffentlicht in: | The FEBS journal 2007-09, Vol.274 (18), p.4825-4836 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 4836 |
---|---|
container_issue | 18 |
container_start_page | 4825 |
container_title | The FEBS journal |
container_volume | 274 |
creator | Geden, Sandra E Gardner, Richard A Fabbrini, M. Serena Ohashi, Masato Phanstiel IV, Otto Teter, Ken |
description | Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes. The latter process may represent a rate-limiting step for intoxication and would therefore directly affect toxin potency. In the present study, we document two treatments (shock with dimethylsulfoxide and lipopolyamine coadministration) that generate substantial cellular sensitization to saporin/uPA-saporin. With the use of lysosome-endosome X (LEX)1 and LEX2 mutant cell lines, an endosomal trafficking step preceding cargo delivery to the late endosomes was identified as a major site for the dimethylsulfoxide-facilitated entry of saporin into the cytosol. Dimethylsulfoxide and lipopolyamines are known to disrupt the integrity of endosome membranes, so these reagents could facilitate the rapid movement of toxin from permeabilized endosomes to the cytosol. However, the same pattern of toxin sensitization was not observed for dimethylsulfoxide- or lipopolyamine-treated cells exposed to diphtheria toxin, ricin, or the catalytic A chain of ricin. The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments. |
doi_str_mv | 10.1111/j.1742-4658.2007.06008.x |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_20807829</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1330028531</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5008-2d98373687a8a1b1d0579fa1ff18aedc10af0e988cb7acea8b272add3cd0b4223</originalsourceid><addsrcrecordid>eNqNkUFr3DAQhU1padKkf6E1PfS2zki2V_Kl0ISkCSz0kAR6E2NZSmRsyZVksvvvK3eXLfQUIaER75uHpJdlOYGCpHHRF4RVdFWta15QAFbAGoAX2zfZ6VF4e6yrXyfZhxB6gLKumuZ9dkIYI1VNytPMbczkJjfscDRW5dErjKOyMTdWpjqokMdnlSutjUS5y51OSnTbdIrG2fzFxOc84OS8sTnaLq00Y5KtVP6oSGf7-QmjOs_eaRyC-njYz7LHm-uHq9vV5uePu6vvm5Ws00tWtGt4yco1Z8iRtKSDmjUaidaEo-okAdSgGs5ly1Aq5C1lFLuulB20FaXlWfZ17zt593tWIYrRBKmGAa1ycxAUODBOmwR--Q_s3extultiKkqqBhaI7yHpXQheaTF5M6LfCQJiSUT0YvlssXy8WBIRfxMR29T66eA_t6Pq_jUeIkjAtz3wYga1e7WxuLm-vF_KZPB5b6DRCXzyJojHewqkTCKUa6jLPzvopbM</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>204214909</pqid></control><display><type>article</type><title>Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Wiley Free Content</source><source>IngentaConnect Free/Open Access Journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Geden, Sandra E ; Gardner, Richard A ; Fabbrini, M. Serena ; Ohashi, Masato ; Phanstiel IV, Otto ; Teter, Ken</creator><creatorcontrib>Geden, Sandra E ; Gardner, Richard A ; Fabbrini, M. Serena ; Ohashi, Masato ; Phanstiel IV, Otto ; Teter, Ken</creatorcontrib><description>Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes. The latter process may represent a rate-limiting step for intoxication and would therefore directly affect toxin potency. In the present study, we document two treatments (shock with dimethylsulfoxide and lipopolyamine coadministration) that generate substantial cellular sensitization to saporin/uPA-saporin. With the use of lysosome-endosome X (LEX)1 and LEX2 mutant cell lines, an endosomal trafficking step preceding cargo delivery to the late endosomes was identified as a major site for the dimethylsulfoxide-facilitated entry of saporin into the cytosol. Dimethylsulfoxide and lipopolyamines are known to disrupt the integrity of endosome membranes, so these reagents could facilitate the rapid movement of toxin from permeabilized endosomes to the cytosol. However, the same pattern of toxin sensitization was not observed for dimethylsulfoxide- or lipopolyamine-treated cells exposed to diphtheria toxin, ricin, or the catalytic A chain of ricin. The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments.</description><identifier>ISSN: 1742-464X</identifier><identifier>EISSN: 1742-4658</identifier><identifier>DOI: 10.1111/j.1742-4658.2007.06008.x</identifier><identifier>PMID: 17714513</identifier><language>eng</language><publisher>Oxford, UK: Oxford, UK : Blackwell Publishing Ltd</publisher><subject>Animals ; anticancer therapy ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - toxicity ; Cancer ; Cell Line ; Chemotherapy ; CHO Cells ; Cold Temperature ; Cricetinae ; Cricetulus ; Dimethyl Sulfoxide - pharmacology ; Dimethyl Sulfoxide - toxicity ; Endocytosis ; Endocytosis - drug effects ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; endosome ; Endosomes - metabolism ; intracellular trafficking ; Lysosomes - metabolism ; Molecular biology ; plant ribosome‐inactivating protein ; polyamine ; Polyamines - pharmacology ; Proteins ; Ribosome Inactivating Proteins, Type 1 - chemistry ; Ribosome Inactivating Proteins, Type 1 - toxicity ; Ricin - toxicity ; Toxins ; Urokinase-Type Plasminogen Activator - chemistry ; Urokinase-Type Plasminogen Activator - toxicity</subject><ispartof>The FEBS journal, 2007-09, Vol.274 (18), p.4825-4836</ispartof><rights>2007 The Authors Journal compilation 2007 FEBS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5008-2d98373687a8a1b1d0579fa1ff18aedc10af0e988cb7acea8b272add3cd0b4223</citedby><cites>FETCH-LOGICAL-c5008-2d98373687a8a1b1d0579fa1ff18aedc10af0e988cb7acea8b272add3cd0b4223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1742-4658.2007.06008.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1742-4658.2007.06008.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27903,27904,45553,45554,46387,46811</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17714513$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geden, Sandra E</creatorcontrib><creatorcontrib>Gardner, Richard A</creatorcontrib><creatorcontrib>Fabbrini, M. Serena</creatorcontrib><creatorcontrib>Ohashi, Masato</creatorcontrib><creatorcontrib>Phanstiel IV, Otto</creatorcontrib><creatorcontrib>Teter, Ken</creatorcontrib><title>Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate</title><title>The FEBS journal</title><addtitle>FEBS J</addtitle><description>Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes. The latter process may represent a rate-limiting step for intoxication and would therefore directly affect toxin potency. In the present study, we document two treatments (shock with dimethylsulfoxide and lipopolyamine coadministration) that generate substantial cellular sensitization to saporin/uPA-saporin. With the use of lysosome-endosome X (LEX)1 and LEX2 mutant cell lines, an endosomal trafficking step preceding cargo delivery to the late endosomes was identified as a major site for the dimethylsulfoxide-facilitated entry of saporin into the cytosol. Dimethylsulfoxide and lipopolyamines are known to disrupt the integrity of endosome membranes, so these reagents could facilitate the rapid movement of toxin from permeabilized endosomes to the cytosol. However, the same pattern of toxin sensitization was not observed for dimethylsulfoxide- or lipopolyamine-treated cells exposed to diphtheria toxin, ricin, or the catalytic A chain of ricin. The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments.</description><subject>Animals</subject><subject>anticancer therapy</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Cancer</subject><subject>Cell Line</subject><subject>Chemotherapy</subject><subject>CHO Cells</subject><subject>Cold Temperature</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Dimethyl Sulfoxide - pharmacology</subject><subject>Dimethyl Sulfoxide - toxicity</subject><subject>Endocytosis</subject><subject>Endocytosis - drug effects</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>endosome</subject><subject>Endosomes - metabolism</subject><subject>intracellular trafficking</subject><subject>Lysosomes - metabolism</subject><subject>Molecular biology</subject><subject>plant ribosome‐inactivating protein</subject><subject>polyamine</subject><subject>Polyamines - pharmacology</subject><subject>Proteins</subject><subject>Ribosome Inactivating Proteins, Type 1 - chemistry</subject><subject>Ribosome Inactivating Proteins, Type 1 - toxicity</subject><subject>Ricin - toxicity</subject><subject>Toxins</subject><subject>Urokinase-Type Plasminogen Activator - chemistry</subject><subject>Urokinase-Type Plasminogen Activator - toxicity</subject><issn>1742-464X</issn><issn>1742-4658</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFr3DAQhU1padKkf6E1PfS2zki2V_Kl0ISkCSz0kAR6E2NZSmRsyZVksvvvK3eXLfQUIaER75uHpJdlOYGCpHHRF4RVdFWta15QAFbAGoAX2zfZ6VF4e6yrXyfZhxB6gLKumuZ9dkIYI1VNytPMbczkJjfscDRW5dErjKOyMTdWpjqokMdnlSutjUS5y51OSnTbdIrG2fzFxOc84OS8sTnaLq00Y5KtVP6oSGf7-QmjOs_eaRyC-njYz7LHm-uHq9vV5uePu6vvm5Ws00tWtGt4yco1Z8iRtKSDmjUaidaEo-okAdSgGs5ly1Aq5C1lFLuulB20FaXlWfZ17zt593tWIYrRBKmGAa1ycxAUODBOmwR--Q_s3extultiKkqqBhaI7yHpXQheaTF5M6LfCQJiSUT0YvlssXy8WBIRfxMR29T66eA_t6Pq_jUeIkjAtz3wYga1e7WxuLm-vF_KZPB5b6DRCXzyJojHewqkTCKUa6jLPzvopbM</recordid><startdate>200709</startdate><enddate>200709</enddate><creator>Geden, Sandra E</creator><creator>Gardner, Richard A</creator><creator>Fabbrini, M. Serena</creator><creator>Ohashi, Masato</creator><creator>Phanstiel IV, Otto</creator><creator>Teter, Ken</creator><general>Oxford, UK : Blackwell Publishing Ltd</general><general>Blackwell Publishing Ltd</general><scope>FBQ</scope><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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope></search><sort><creationdate>200709</creationdate><title>Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate</title><author>Geden, Sandra E ; Gardner, Richard A ; Fabbrini, M. Serena ; Ohashi, Masato ; Phanstiel IV, Otto ; Teter, Ken</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5008-2d98373687a8a1b1d0579fa1ff18aedc10af0e988cb7acea8b272add3cd0b4223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>anticancer therapy</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - toxicity</topic><topic>Cancer</topic><topic>Cell Line</topic><topic>Chemotherapy</topic><topic>CHO Cells</topic><topic>Cold Temperature</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Dimethyl Sulfoxide - pharmacology</topic><topic>Dimethyl Sulfoxide - toxicity</topic><topic>Endocytosis</topic><topic>Endocytosis - drug effects</topic><topic>Endoplasmic Reticulum - drug effects</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>endosome</topic><topic>Endosomes - metabolism</topic><topic>intracellular trafficking</topic><topic>Lysosomes - metabolism</topic><topic>Molecular biology</topic><topic>plant ribosome‐inactivating protein</topic><topic>polyamine</topic><topic>Polyamines - pharmacology</topic><topic>Proteins</topic><topic>Ribosome Inactivating Proteins, Type 1 - chemistry</topic><topic>Ribosome Inactivating Proteins, Type 1 - toxicity</topic><topic>Ricin - toxicity</topic><topic>Toxins</topic><topic>Urokinase-Type Plasminogen Activator - chemistry</topic><topic>Urokinase-Type Plasminogen Activator - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geden, Sandra E</creatorcontrib><creatorcontrib>Gardner, Richard A</creatorcontrib><creatorcontrib>Fabbrini, M. Serena</creatorcontrib><creatorcontrib>Ohashi, Masato</creatorcontrib><creatorcontrib>Phanstiel IV, Otto</creatorcontrib><creatorcontrib>Teter, Ken</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><jtitle>The FEBS journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geden, Sandra E</au><au>Gardner, Richard A</au><au>Fabbrini, M. Serena</au><au>Ohashi, Masato</au><au>Phanstiel IV, Otto</au><au>Teter, Ken</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate</atitle><jtitle>The FEBS journal</jtitle><addtitle>FEBS J</addtitle><date>2007-09</date><risdate>2007</risdate><volume>274</volume><issue>18</issue><spage>4825</spage><epage>4836</epage><pages>4825-4836</pages><issn>1742-464X</issn><eissn>1742-4658</eissn><abstract>Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes. The latter process may represent a rate-limiting step for intoxication and would therefore directly affect toxin potency. In the present study, we document two treatments (shock with dimethylsulfoxide and lipopolyamine coadministration) that generate substantial cellular sensitization to saporin/uPA-saporin. With the use of lysosome-endosome X (LEX)1 and LEX2 mutant cell lines, an endosomal trafficking step preceding cargo delivery to the late endosomes was identified as a major site for the dimethylsulfoxide-facilitated entry of saporin into the cytosol. Dimethylsulfoxide and lipopolyamines are known to disrupt the integrity of endosome membranes, so these reagents could facilitate the rapid movement of toxin from permeabilized endosomes to the cytosol. However, the same pattern of toxin sensitization was not observed for dimethylsulfoxide- or lipopolyamine-treated cells exposed to diphtheria toxin, ricin, or the catalytic A chain of ricin. The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments.</abstract><cop>Oxford, UK</cop><pub>Oxford, UK : Blackwell Publishing Ltd</pub><pmid>17714513</pmid><doi>10.1111/j.1742-4658.2007.06008.x</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1742-464X |
ispartof | The FEBS journal, 2007-09, Vol.274 (18), p.4825-4836 |
issn | 1742-464X 1742-4658 |
language | eng |
recordid | cdi_proquest_miscellaneous_20807829 |
source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Wiley Free Content; IngentaConnect Free/Open Access Journals; Free Full-Text Journals in Chemistry |
subjects | Animals anticancer therapy Antineoplastic Agents - chemistry Antineoplastic Agents - toxicity Cancer Cell Line Chemotherapy CHO Cells Cold Temperature Cricetinae Cricetulus Dimethyl Sulfoxide - pharmacology Dimethyl Sulfoxide - toxicity Endocytosis Endocytosis - drug effects Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism endosome Endosomes - metabolism intracellular trafficking Lysosomes - metabolism Molecular biology plant ribosome‐inactivating protein polyamine Polyamines - pharmacology Proteins Ribosome Inactivating Proteins, Type 1 - chemistry Ribosome Inactivating Proteins, Type 1 - toxicity Ricin - toxicity Toxins Urokinase-Type Plasminogen Activator - chemistry Urokinase-Type Plasminogen Activator - toxicity |
title | Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-26T03%3A41%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Lipopolyamine%20treatment%20increases%20the%20efficacy%20of%20intoxication%20with%20saporin%20and%20an%20anticancer%20saporin%20conjugate&rft.jtitle=The%20FEBS%20journal&rft.au=Geden,%20Sandra%20E&rft.date=2007-09&rft.volume=274&rft.issue=18&rft.spage=4825&rft.epage=4836&rft.pages=4825-4836&rft.issn=1742-464X&rft.eissn=1742-4658&rft_id=info:doi/10.1111/j.1742-4658.2007.06008.x&rft_dat=%3Cproquest_cross%3E1330028531%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204214909&rft_id=info:pmid/17714513&rfr_iscdi=true |