DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells
Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inh...
Gespeichert in:
| Veröffentlicht in: | PloS one 2015-12, Vol.10 (12), p.e0145744-e0145744 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e0145744 |
|---|---|
| container_issue | 12 |
| container_start_page | e0145744 |
| container_title | PloS one |
| container_volume | 10 |
| creator | Dolman, M Emmy M van der Ploeg, Ida Koster, Jan Bate-Eya, Laurel Tabe Versteeg, Rogier Caron, Huib N Molenaar, Jan J |
| description | Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization. |
| doi_str_mv | 10.1371/journal.pone.0145744 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1752583045</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A438727580</galeid><doaj_id>oai_doaj_org_article_3d3e95291864404ca49a745b797dcb19</doaj_id><sourcerecordid>A438727580</sourcerecordid><originalsourceid>FETCH-LOGICAL-c692t-deeb33cc2b6530240e862105310004fb39e653acae773721d0fe5c6fdbe055803</originalsourceid><addsrcrecordid>eNqNk11v0zAUhiMEYqPwDxBEQkJw0WLHX8nNpKrjo2JsaAwusRznpHXlxsV2EPDrcddsatEukC9s2c95j_36nCx7itEEE4HfrFzvO2UnG9fBBGHKBKX3smNckWLMC0Tu762PskchrBBipOT8YXZUcIF5Sarj7Pvp-XR8ChvoGuhi_tm7CKbLP5pOBcinIf_kLOjeKp9fKb-AmLfO55eqMS5AF0w0f1Q0rstdm59D711tVYhurfIZWBseZw9aZQM8GeZR9vXd26vZh_HZxfv5bHo21rwq4rgBqAnRuqg5I6igCEpe4HRdjBCibU0qSAdKKxCCiAI3qAWmedvUgBgrERllz3e6G-uCHKwJEgtWsJIgyhIx3xGNUyu58Wat_G_plJHXG84vpPLRaAuSNAQqVlS45JQiqhWtlKCsFpVodJ1MHWUnQ7a-XkOjk3Ne2QPRw5POLOXC_ZSUV1yQMgm8GgS8-9FDiHJtgk6GqQ5cf31vQillmCb0xT_o3a8bqIVKDzBd61JevRWVU0pKUYidS5M7qDQaWBud6qg1af8g4PVBQGIi_IoL1Ycg518u_5-9-HbIvtxjl6BsXAZn-20lhUOQ7kDtXQge2luTMZLbNrhxQ27bQA5tkMKe7X_QbdBN3ZO_3r0BKA</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1752583045</pqid></control><display><type>article</type><title>DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Public Library of Science (PLoS) Journals Open Access</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Dolman, M Emmy M ; van der Ploeg, Ida ; Koster, Jan ; Bate-Eya, Laurel Tabe ; Versteeg, Rogier ; Caron, Huib N ; Molenaar, Jan J</creator><contributor>Cotterill, Sue</contributor><creatorcontrib>Dolman, M Emmy M ; van der Ploeg, Ida ; Koster, Jan ; Bate-Eya, Laurel Tabe ; Versteeg, Rogier ; Caron, Huib N ; Molenaar, Jan J ; Cotterill, Sue</creatorcontrib><description>Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0145744</identifier><identifier>PMID: 26716839</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Breast cancer ; Cancer therapies ; Catalysis ; Cell culture ; Cell cycle ; Cell Line, Tumor ; Cervical cancer ; Chromones - pharmacology ; Combined treatment ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA damage ; DNA Damage - drug effects ; DNA Damage - genetics ; DNA End-Joining Repair - drug effects ; DNA End-Joining Repair - genetics ; DNA repair ; DNA-Activated Protein Kinase - metabolism ; DNA-Binding Proteins - metabolism ; DNA-dependent protein kinase ; Fibroblasts ; Gene expression ; Genetic aspects ; Health aspects ; Homology ; Humans ; I.R. radiation ; Inhibition ; Innovations ; Ionizing radiation ; Kinases ; Methods ; Molecular targeted therapy ; Morpholines - pharmacology ; Neuroblastoma ; Neuroblastoma - drug therapy ; Neuroblastoma - metabolism ; Neuroblastoma - radiotherapy ; Neuroblastoma cells ; Non-homologous end joining ; Nuclear Proteins - metabolism ; Penicillin ; Pretreatment ; Protein kinase C ; Protein kinases ; Proteins ; Radiation ; Radiation therapy ; Radiation Tolerance - genetics ; Radiation, Ionizing ; Radiation-Sensitizing Agents - pharmacology ; Radiosensitization ; Radiotherapy ; Synergistic effect ; Tumor cells ; Tumors</subject><ispartof>PloS one, 2015-12, Vol.10 (12), p.e0145744-e0145744</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Dolman 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 Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Dolman et al 2015 Dolman et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-deeb33cc2b6530240e862105310004fb39e653acae773721d0fe5c6fdbe055803</citedby><cites>FETCH-LOGICAL-c692t-deeb33cc2b6530240e862105310004fb39e653acae773721d0fe5c6fdbe055803</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/PMC4696738/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696738/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23871,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26716839$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cotterill, Sue</contributor><creatorcontrib>Dolman, M Emmy M</creatorcontrib><creatorcontrib>van der Ploeg, Ida</creatorcontrib><creatorcontrib>Koster, Jan</creatorcontrib><creatorcontrib>Bate-Eya, Laurel Tabe</creatorcontrib><creatorcontrib>Versteeg, Rogier</creatorcontrib><creatorcontrib>Caron, Huib N</creatorcontrib><creatorcontrib>Molenaar, Jan J</creatorcontrib><title>DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.</description><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Catalysis</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cervical cancer</subject><subject>Chromones - pharmacology</subject><subject>Combined treatment</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Damage - drug effects</subject><subject>DNA Damage - genetics</subject><subject>DNA End-Joining Repair - drug effects</subject><subject>DNA End-Joining Repair - genetics</subject><subject>DNA repair</subject><subject>DNA-Activated Protein Kinase - metabolism</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>DNA-dependent protein kinase</subject><subject>Fibroblasts</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Homology</subject><subject>Humans</subject><subject>I.R. radiation</subject><subject>Inhibition</subject><subject>Innovations</subject><subject>Ionizing radiation</subject><subject>Kinases</subject><subject>Methods</subject><subject>Molecular targeted therapy</subject><subject>Morpholines - pharmacology</subject><subject>Neuroblastoma</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - metabolism</subject><subject>Neuroblastoma - radiotherapy</subject><subject>Neuroblastoma cells</subject><subject>Non-homologous end joining</subject><subject>Nuclear Proteins - metabolism</subject><subject>Penicillin</subject><subject>Pretreatment</subject><subject>Protein kinase C</subject><subject>Protein kinases</subject><subject>Proteins</subject><subject>Radiation</subject><subject>Radiation therapy</subject><subject>Radiation Tolerance - genetics</subject><subject>Radiation, Ionizing</subject><subject>Radiation-Sensitizing Agents - pharmacology</subject><subject>Radiosensitization</subject><subject>Radiotherapy</subject><subject>Synergistic effect</subject><subject>Tumor cells</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</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>eNqNk11v0zAUhiMEYqPwDxBEQkJw0WLHX8nNpKrjo2JsaAwusRznpHXlxsV2EPDrcddsatEukC9s2c95j_36nCx7itEEE4HfrFzvO2UnG9fBBGHKBKX3smNckWLMC0Tu762PskchrBBipOT8YXZUcIF5Sarj7Pvp-XR8ChvoGuhi_tm7CKbLP5pOBcinIf_kLOjeKp9fKb-AmLfO55eqMS5AF0w0f1Q0rstdm59D711tVYhurfIZWBseZw9aZQM8GeZR9vXd26vZh_HZxfv5bHo21rwq4rgBqAnRuqg5I6igCEpe4HRdjBCibU0qSAdKKxCCiAI3qAWmedvUgBgrERllz3e6G-uCHKwJEgtWsJIgyhIx3xGNUyu58Wat_G_plJHXG84vpPLRaAuSNAQqVlS45JQiqhWtlKCsFpVodJ1MHWUnQ7a-XkOjk3Ne2QPRw5POLOXC_ZSUV1yQMgm8GgS8-9FDiHJtgk6GqQ5cf31vQillmCb0xT_o3a8bqIVKDzBd61JevRWVU0pKUYidS5M7qDQaWBud6qg1af8g4PVBQGIi_IoL1Ycg518u_5-9-HbIvtxjl6BsXAZn-20lhUOQ7kDtXQge2luTMZLbNrhxQ27bQA5tkMKe7X_QbdBN3ZO_3r0BKA</recordid><startdate>20151230</startdate><enddate>20151230</enddate><creator>Dolman, M Emmy M</creator><creator>van der Ploeg, Ida</creator><creator>Koster, Jan</creator><creator>Bate-Eya, Laurel Tabe</creator><creator>Versteeg, Rogier</creator><creator>Caron, Huib N</creator><creator>Molenaar, Jan J</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>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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20151230</creationdate><title>DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells</title><author>Dolman, M Emmy M ; van der Ploeg, Ida ; Koster, Jan ; Bate-Eya, Laurel Tabe ; Versteeg, Rogier ; Caron, Huib N ; Molenaar, Jan J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-deeb33cc2b6530240e862105310004fb39e653acae773721d0fe5c6fdbe055803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Breast cancer</topic><topic>Cancer therapies</topic><topic>Catalysis</topic><topic>Cell culture</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cervical cancer</topic><topic>Chromones - pharmacology</topic><topic>Combined treatment</topic><topic>Deoxyribonucleic acid</topic><topic>Development and progression</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA Damage - drug effects</topic><topic>DNA Damage - genetics</topic><topic>DNA End-Joining Repair - drug effects</topic><topic>DNA End-Joining Repair - genetics</topic><topic>DNA repair</topic><topic>DNA-Activated Protein Kinase - metabolism</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>DNA-dependent protein kinase</topic><topic>Fibroblasts</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Homology</topic><topic>Humans</topic><topic>I.R. radiation</topic><topic>Inhibition</topic><topic>Innovations</topic><topic>Ionizing radiation</topic><topic>Kinases</topic><topic>Methods</topic><topic>Molecular targeted therapy</topic><topic>Morpholines - pharmacology</topic><topic>Neuroblastoma</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - metabolism</topic><topic>Neuroblastoma - radiotherapy</topic><topic>Neuroblastoma cells</topic><topic>Non-homologous end joining</topic><topic>Nuclear Proteins - metabolism</topic><topic>Penicillin</topic><topic>Pretreatment</topic><topic>Protein kinase C</topic><topic>Protein kinases</topic><topic>Proteins</topic><topic>Radiation</topic><topic>Radiation therapy</topic><topic>Radiation Tolerance - genetics</topic><topic>Radiation, Ionizing</topic><topic>Radiation-Sensitizing Agents - pharmacology</topic><topic>Radiosensitization</topic><topic>Radiotherapy</topic><topic>Synergistic effect</topic><topic>Tumor cells</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dolman, M Emmy M</creatorcontrib><creatorcontrib>van der Ploeg, Ida</creatorcontrib><creatorcontrib>Koster, Jan</creatorcontrib><creatorcontrib>Bate-Eya, Laurel Tabe</creatorcontrib><creatorcontrib>Versteeg, Rogier</creatorcontrib><creatorcontrib>Caron, Huib N</creatorcontrib><creatorcontrib>Molenaar, Jan J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dolman, M Emmy M</au><au>van der Ploeg, Ida</au><au>Koster, Jan</au><au>Bate-Eya, Laurel Tabe</au><au>Versteeg, Rogier</au><au>Caron, Huib N</au><au>Molenaar, Jan J</au><au>Cotterill, Sue</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-12-30</date><risdate>2015</risdate><volume>10</volume><issue>12</issue><spage>e0145744</spage><epage>e0145744</epage><pages>e0145744-e0145744</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26716839</pmid><doi>10.1371/journal.pone.0145744</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-12, Vol.10 (12), p.e0145744-e0145744 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1752583045 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Apoptosis Apoptosis - drug effects Apoptosis - genetics Breast cancer Cancer therapies Catalysis Cell culture Cell cycle Cell Line, Tumor Cervical cancer Chromones - pharmacology Combined treatment Deoxyribonucleic acid Development and progression DNA DNA damage DNA Damage - drug effects DNA Damage - genetics DNA End-Joining Repair - drug effects DNA End-Joining Repair - genetics DNA repair DNA-Activated Protein Kinase - metabolism DNA-Binding Proteins - metabolism DNA-dependent protein kinase Fibroblasts Gene expression Genetic aspects Health aspects Homology Humans I.R. radiation Inhibition Innovations Ionizing radiation Kinases Methods Molecular targeted therapy Morpholines - pharmacology Neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - metabolism Neuroblastoma - radiotherapy Neuroblastoma cells Non-homologous end joining Nuclear Proteins - metabolism Penicillin Pretreatment Protein kinase C Protein kinases Proteins Radiation Radiation therapy Radiation Tolerance - genetics Radiation, Ionizing Radiation-Sensitizing Agents - pharmacology Radiosensitization Radiotherapy Synergistic effect Tumor cells Tumors |
| title | DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T01%3A35%3A31IST&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=DNA-Dependent%20Protein%20Kinase%20As%20Molecular%20Target%20for%20Radiosensitization%20of%20Neuroblastoma%20Cells&rft.jtitle=PloS%20one&rft.au=Dolman,%20M%20Emmy%20M&rft.date=2015-12-30&rft.volume=10&rft.issue=12&rft.spage=e0145744&rft.epage=e0145744&rft.pages=e0145744-e0145744&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0145744&rft_dat=%3Cgale_plos_%3EA438727580%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=1752583045&rft_id=info:pmid/26716839&rft_galeid=A438727580&rft_doaj_id=oai_doaj_org_article_3d3e95291864404ca49a745b797dcb19&rfr_iscdi=true |