A first-generation multi-functional cytokine for simultaneous optical tracking and tumor therapy
Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targete...
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| Veröffentlicht in: | PloS one 2012-07, Vol.7 (7), p.e40234 |
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| creator | Hingtgen, Shawn Kasmieh, Randa Elbayly, Elizabeth Nesterenko, Irina Figueiredo, Jose-Luiz Dash, Rupesh Sarkar, Devanand Hall, David Kozakov, Dima Vajda, Sandor Fisher, Paul B Shah, Khalid |
| description | Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. Collectively, these studies define a promising new approach to treating highly aggressive cancers, including GBM, using the optimized therapeutic molecule SM7L. |
| doi_str_mv | 10.1371/journal.pone.0040234 |
| format | Article |
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Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. Collectively, these studies define a promising new approach to treating highly aggressive cancers, including GBM, using the optimized therapeutic molecule SM7L.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0040234</identifier><identifier>PMID: 22808125</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoviruses ; Animals ; Anticancer properties ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Biology ; Biomedical engineering ; Brain ; Brain cancer ; Brain Neoplasms - diagnosis ; Brain Neoplasms - drug therapy ; Brain Neoplasms - pathology ; Brain tumors ; Cancer ; Cancer therapies ; Cancer treatment ; Caspase ; Cell Death - drug effects ; Cell Line, Tumor ; Colorectal cancer ; Cytokines ; Deoxyribonucleic acid ; Diagnostic systems ; Disease Progression ; DNA ; Drug Delivery Systems ; Effectiveness ; Engineering ; Gene expression ; Glioblastoma ; Glioblastoma - diagnosis ; Glioblastoma - drug therapy ; Glioblastoma - pathology ; Glioblastoma multiforme ; Gliomas ; Health aspects ; Humans ; Interleukin 24 ; Interleukins - pharmacokinetics ; Interleukins - pharmacology ; Interleukins - therapeutic use ; Laboratories ; Lung cancer ; Mda-7 protein ; Medical diagnosis ; Medical schools ; Medicine ; Melanoma ; Metabolic pathways ; Mice ; Models, Biological ; Models, Molecular ; Neural Stem Cells - drug effects ; Neural Stem Cells - metabolism ; Neurodegeneration ; Optical Phenomena ; Optical tracking ; Pharmacokinetics ; Pharmacology ; Photon emission ; Reproducibility of Results ; Signal Transduction - drug effects ; Stem cell transplantation ; Stem cells ; Therapy ; Transplants & implants ; Treatment Outcome ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts ; Xenotransplantation</subject><ispartof>PloS one, 2012-07, Vol.7 (7), p.e40234</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Hingtgen 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>Hingtgen et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-fada5fb8854448d0eadeaad100c10efee7f67fef8ba65c17d9e5b3b1fcf41ac73</citedby><cites>FETCH-LOGICAL-c692t-fada5fb8854448d0eadeaad100c10efee7f67fef8ba65c17d9e5b3b1fcf41ac73</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/PMC3394792/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394792/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22808125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Najbauer, Joseph</contributor><creatorcontrib>Hingtgen, Shawn</creatorcontrib><creatorcontrib>Kasmieh, Randa</creatorcontrib><creatorcontrib>Elbayly, Elizabeth</creatorcontrib><creatorcontrib>Nesterenko, Irina</creatorcontrib><creatorcontrib>Figueiredo, Jose-Luiz</creatorcontrib><creatorcontrib>Dash, Rupesh</creatorcontrib><creatorcontrib>Sarkar, Devanand</creatorcontrib><creatorcontrib>Hall, David</creatorcontrib><creatorcontrib>Kozakov, Dima</creatorcontrib><creatorcontrib>Vajda, Sandor</creatorcontrib><creatorcontrib>Fisher, Paul B</creatorcontrib><creatorcontrib>Shah, Khalid</creatorcontrib><title>A first-generation multi-functional cytokine for simultaneous optical tracking and tumor therapy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. 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diagnosis</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - pathology</subject><subject>Glioblastoma multiforme</subject><subject>Gliomas</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Interleukin 24</subject><subject>Interleukins - pharmacokinetics</subject><subject>Interleukins - pharmacology</subject><subject>Interleukins - therapeutic use</subject><subject>Laboratories</subject><subject>Lung cancer</subject><subject>Mda-7 protein</subject><subject>Medical diagnosis</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Melanoma</subject><subject>Metabolic pathways</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Models, Molecular</subject><subject>Neural Stem Cells - drug effects</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neurodegeneration</subject><subject>Optical Phenomena</subject><subject>Optical tracking</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Photon emission</subject><subject>Reproducibility of Results</subject><subject>Signal Transduction - drug effects</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Therapy</subject><subject>Transplants & implants</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</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>eNqNkluL1DAYhoso7jr6D0QLguBFx5x6uhGGxcPAwoKn2_g1TToZ22RMUnH-vanTXaagILnI6fnefHl5k-QpRmtMS_x6b0dnoF8frJFrhBgilN1LLnFNSVYQRO-frS-SR97vEcppVRQPkwtCKlRhkl8m3zap0s6HrJNGOgjamnQY-6AzNRoxbaFPxTHY79rIVFmXej3dg5F29Kk9BC0iERyISHQpmDYN4xC5sIt6h-Pj5IGC3ssn87xKvrx7-_nqQ3Z98357tbnORFGTkCloIVdNVeWMsapFEloJ0GKEBEZSSVmqolRSVQ0UucBlW8u8oQ1WQjEMoqSr5PlJ99Bbz2dzPMeU5KwuCC4isT0RrYU9Pzg9gDtyC5r_ObCu4-Did3rJG0ybssVNpeqGARMNNKqoSGwguqwEiVpv5tfGZpCtkCY60C9ElzdG73hnf3JKa1bWk8CLWcDZH6P04R8tz1QHsSttlJ2MHrQXfMPKEmPK4lgl679QcbRy0CLGQ-l4vih4tSiITJC_Qgej93z76eP_szdfl-zLM3YnoQ87b_txipFfguwECme9d1LdOYcRn9J96waf0s3ndMeyZ-eu3xXdxpn-Bnif-NE</recordid><startdate>20120711</startdate><enddate>20120711</enddate><creator>Hingtgen, Shawn</creator><creator>Kasmieh, Randa</creator><creator>Elbayly, Elizabeth</creator><creator>Nesterenko, Irina</creator><creator>Figueiredo, Jose-Luiz</creator><creator>Dash, Rupesh</creator><creator>Sarkar, Devanand</creator><creator>Hall, David</creator><creator>Kozakov, Dima</creator><creator>Vajda, Sandor</creator><creator>Fisher, Paul B</creator><creator>Shah, Khalid</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120711</creationdate><title>A first-generation multi-functional cytokine for simultaneous optical tracking and tumor therapy</title><author>Hingtgen, Shawn ; Kasmieh, Randa ; Elbayly, Elizabeth ; Nesterenko, Irina ; Figueiredo, Jose-Luiz ; Dash, Rupesh ; Sarkar, Devanand ; Hall, David ; Kozakov, Dima ; Vajda, Sandor ; Fisher, Paul B ; Shah, Khalid</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-fada5fb8854448d0eadeaad100c10efee7f67fef8ba65c17d9e5b3b1fcf41ac73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenoviruses</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - 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Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. Collectively, these studies define a promising new approach to treating highly aggressive cancers, including GBM, using the optimized therapeutic molecule SM7L.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22808125</pmid><doi>10.1371/journal.pone.0040234</doi><tpages>e40234</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-07, Vol.7 (7), p.e40234 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325496216 |
| 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 | Adenoviruses Animals Anticancer properties Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Apoptosis Biology Biomedical engineering Brain Brain cancer Brain Neoplasms - diagnosis Brain Neoplasms - drug therapy Brain Neoplasms - pathology Brain tumors Cancer Cancer therapies Cancer treatment Caspase Cell Death - drug effects Cell Line, Tumor Colorectal cancer Cytokines Deoxyribonucleic acid Diagnostic systems Disease Progression DNA Drug Delivery Systems Effectiveness Engineering Gene expression Glioblastoma Glioblastoma - diagnosis Glioblastoma - drug therapy Glioblastoma - pathology Glioblastoma multiforme Gliomas Health aspects Humans Interleukin 24 Interleukins - pharmacokinetics Interleukins - pharmacology Interleukins - therapeutic use Laboratories Lung cancer Mda-7 protein Medical diagnosis Medical schools Medicine Melanoma Metabolic pathways Mice Models, Biological Models, Molecular Neural Stem Cells - drug effects Neural Stem Cells - metabolism Neurodegeneration Optical Phenomena Optical tracking Pharmacokinetics Pharmacology Photon emission Reproducibility of Results Signal Transduction - drug effects Stem cell transplantation Stem cells Therapy Transplants & implants Treatment Outcome Tumors Xenograft Model Antitumor Assays Xenografts Xenotransplantation |
| title | A first-generation multi-functional cytokine for simultaneous optical tracking and tumor therapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T14%3A36%3A52IST&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=A%20first-generation%20multi-functional%20cytokine%20for%20simultaneous%20optical%20tracking%20and%20tumor%20therapy&rft.jtitle=PloS%20one&rft.au=Hingtgen,%20Shawn&rft.date=2012-07-11&rft.volume=7&rft.issue=7&rft.spage=e40234&rft.pages=e40234-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0040234&rft_dat=%3Cgale_plos_%3EA477113434%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=1325496216&rft_id=info:pmid/22808125&rft_galeid=A477113434&rft_doaj_id=oai_doaj_org_article_b13b7d1b8f9b4a4cbabf6827fe023fc2&rfr_iscdi=true |