The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage
Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisat...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e35436 |
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| creator | Zaidi, Shane McLaughlin, Martin Bhide, Shreerang A Eccles, Suzanne A Workman, Paul Nutting, Christopher M Huddart, Robert A Harrington, Kevin J |
| description | Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.
NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = |
| doi_str_mv | 10.1371/journal.pone.0035436 |
| format | Article |
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NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.
These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0035436</identifier><identifier>PMID: 22523597</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Animals ; Anticancer properties ; Antineoplastic Agents - pharmacology ; Antitumor activity ; Apoptosis ; Biology ; Biotechnology ; Cell cycle ; Cell Cycle Checkpoints ; Cell division ; Cell Line, Tumor ; Cell survival ; CHK1 protein ; Combinatorial analysis ; Deoxyribonucleic acid ; Depletion ; DNA ; DNA damage ; DNA Damage - physiology ; DNA repair ; DNA Repair - drug effects ; Female ; Head ; Head & neck cancer ; Head and neck cancer ; Heat shock proteins ; Homologous Recombination ; Homology ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; Hsp90 protein ; Humans ; Inhibitor drugs ; Inhibitors ; Isoxazoles - pharmacology ; Kinases ; Laboratories ; Leukemia ; Lung cancer ; Medical research ; Medicine ; Melanoma ; Metastasis ; Mice ; Mice, Nude ; Prostate ; Proteins ; Radiation ; Radiation (Physics) ; Radiation damage ; Radiation effects ; Radiation-Sensitizing Agents - pharmacology ; Radioresistance ; Radiosensitization ; Repair ; Resorcinols - pharmacology ; Senescence ; Signal transduction ; Squamous cell carcinoma ; Survival ; Targeted cancer therapy ; Xenografts</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e35436</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Zaidi 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>Zaidi et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-6ef5f14213c60baf786ef992133f00cc8c18d752112e9f27821b5462a25b05d3</citedby><cites>FETCH-LOGICAL-c692t-6ef5f14213c60baf786ef992133f00cc8c18d752112e9f27821b5462a25b05d3</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/PMC3327673/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327673/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22523597$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zaidi, Shane</creatorcontrib><creatorcontrib>McLaughlin, Martin</creatorcontrib><creatorcontrib>Bhide, Shreerang A</creatorcontrib><creatorcontrib>Eccles, Suzanne A</creatorcontrib><creatorcontrib>Workman, Paul</creatorcontrib><creatorcontrib>Nutting, Christopher M</creatorcontrib><creatorcontrib>Huddart, Robert A</creatorcontrib><creatorcontrib>Harrington, Kevin J</creatorcontrib><title>The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.
NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.
These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific.</description><subject>Aberration</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints</subject><subject>Cell division</subject><subject>Cell Line, Tumor</subject><subject>Cell survival</subject><subject>CHK1 protein</subject><subject>Combinatorial analysis</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Damage - physiology</subject><subject>DNA repair</subject><subject>DNA Repair - drug effects</subject><subject>Female</subject><subject>Head</subject><subject>Head & neck cancer</subject><subject>Head and neck cancer</subject><subject>Heat shock proteins</subject><subject>Homologous Recombination</subject><subject>Homology</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>Hsp90 protein</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Inhibitors</subject><subject>Isoxazoles - pharmacology</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Leukemia</subject><subject>Lung cancer</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Melanoma</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Radiation</subject><subject>Radiation (Physics)</subject><subject>Radiation damage</subject><subject>Radiation effects</subject><subject>Radiation-Sensitizing Agents - pharmacology</subject><subject>Radioresistance</subject><subject>Radiosensitization</subject><subject>Repair</subject><subject>Resorcinols - pharmacology</subject><subject>Senescence</subject><subject>Signal transduction</subject><subject>Squamous cell carcinoma</subject><subject>Survival</subject><subject>Targeted cancer therapy</subject><subject>Xenografts</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>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QDguDFjPlueyMM68cOLLuLOy54FdI0bTO0zZikq-OP8DebOt1lBhQkF0lOnvMmeTknSZ4jOEckRW_XdnC9bOcb2-s5hIRRwh8kxygneMYxJA_31kfJE-_XEDKScf44OcKYYcLy9Dj5tWo0OLu-yiEwfWMKE6wDFzdXs8WXrznGwMnSWK97b4L5qT0otkAWztYyGNsDW4HGdra1tR08cFrZrjD97sxpP7TB9HUUBl3UDUYB3Qe3Bd9NaMDQR8K2t7oE7y8WoJSdrPXT5FElW6-fTfNJsvr4YXV6Nju__LQ8XZzPFM9xmHFdsQpRjIjisJBVmsVInsc9qSBUKlMoK1OGEcI6r3CaYVQwyrHErICsJCfJy53sprVeTE56gQimLCU0x5FY7ojSyrXYONNJtxVWGvEnYF0tpIs_arWAmWQZl0ilvKCM6pzSDEtdSVrlheIkar2bbhuKTpdqNEG2B6KHJ71pRG1vBSE45eko8GoScPbboH34x5MnqpbxVaavbBRTnfFKLGiawgxTMmrN_0LFUerOqFhLlYnxg4Q3BwmRCfpHqOXgvVhef_5_9vLmkH29xzZatqGJ9TCMxeMPQboDlbPeO13dO4egGFvhzg0xtoKYWiGmvdh3_T7prvbJb9lsBIg</recordid><startdate>20120416</startdate><enddate>20120416</enddate><creator>Zaidi, Shane</creator><creator>McLaughlin, Martin</creator><creator>Bhide, Shreerang A</creator><creator>Eccles, Suzanne A</creator><creator>Workman, Paul</creator><creator>Nutting, Christopher M</creator><creator>Huddart, Robert A</creator><creator>Harrington, Kevin 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>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>20120416</creationdate><title>The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage</title><author>Zaidi, Shane ; McLaughlin, Martin ; Bhide, Shreerang A ; Eccles, Suzanne A ; Workman, Paul ; Nutting, Christopher M ; Huddart, Robert A ; Harrington, Kevin J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-6ef5f14213c60baf786ef992133f00cc8c18d752112e9f27821b5462a25b05d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Aberration</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - 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HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.
NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.
These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22523597</pmid><doi>10.1371/journal.pone.0035436</doi><tpages>e35436</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | PloS one, 2012-04, Vol.7 (4), p.e35436 |
| issn | 1932-6203 1932-6203 |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; Full-Text Journals in Chemistry (Open access); PubMed Central; Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Aberration Animals Anticancer properties Antineoplastic Agents - pharmacology Antitumor activity Apoptosis Biology Biotechnology Cell cycle Cell Cycle Checkpoints Cell division Cell Line, Tumor Cell survival CHK1 protein Combinatorial analysis Deoxyribonucleic acid Depletion DNA DNA damage DNA Damage - physiology DNA repair DNA Repair - drug effects Female Head Head & neck cancer Head and neck cancer Heat shock proteins Homologous Recombination Homology HSP90 Heat-Shock Proteins - antagonists & inhibitors Hsp90 protein Humans Inhibitor drugs Inhibitors Isoxazoles - pharmacology Kinases Laboratories Leukemia Lung cancer Medical research Medicine Melanoma Metastasis Mice Mice, Nude Prostate Proteins Radiation Radiation (Physics) Radiation damage Radiation effects Radiation-Sensitizing Agents - pharmacology Radioresistance Radiosensitization Repair Resorcinols - pharmacology Senescence Signal transduction Squamous cell carcinoma Survival Targeted cancer therapy Xenografts |
| title | The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T16%3A43%3A57IST&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=The%20HSP90%20inhibitor%20NVP-AUY922%20radiosensitizes%20by%20abrogation%20of%20homologous%20recombination%20resulting%20in%20mitotic%20entry%20with%20unresolved%20DNA%20damage&rft.jtitle=PloS%20one&rft.au=Zaidi,%20Shane&rft.date=2012-04-16&rft.volume=7&rft.issue=4&rft.spage=e35436&rft.pages=e35436-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0035436&rft_dat=%3Cgale_plos_%3EA477082433%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=1324573492&rft_id=info:pmid/22523597&rft_galeid=A477082433&rft_doaj_id=oai_doaj_org_article_08a586a1c76b454e94482aefa4f9bc63&rfr_iscdi=true |