Comparison of KP1019 and NAMI-A in tumour-mimetic environments
NAMI-A and KP1019 are Ru III -based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru II . The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic...
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| Veröffentlicht in: | Metallomics 2016-08, Vol.8 (8), p.762-773 |
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| creator | Gransbury, Gemma K Kappen, Peter Glover, Chris J Hughes, James N Levina, Aviva Lay, Peter A Musgrave, Ian F Harris, Hugh H |
| description | NAMI-A and KP1019 are Ru
III
-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru
II
. The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 μm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively-coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru
III
to Ru
II
in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive.
Biotransformations of Ru(
iii
) anticancer drugs are compared under a range of controlled hypoxia levels provided by spheroids at different sizes. |
| doi_str_mv | 10.1039/c6mt00145a |
| format | Article |
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III
-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru
II
. The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 μm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively-coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru
III
to Ru
II
in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive.
Biotransformations of Ru(
iii
) anticancer drugs are compared under a range of controlled hypoxia levels provided by spheroids at different sizes.</description><identifier>ISSN: 1756-5901</identifier><identifier>EISSN: 1756-591X</identifier><identifier>DOI: 10.1039/c6mt00145a</identifier><identifier>PMID: 27460862</identifier><language>eng</language><publisher>England</publisher><subject>Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Dimethyl Sulfoxide - analogs & derivatives ; Dimethyl Sulfoxide - chemistry ; Dimethyl Sulfoxide - pharmacology ; Humans ; Hypoxia - physiopathology ; Indazoles - chemistry ; Indazoles - pharmacology ; Neuroblastoma - drug therapy ; Neuroblastoma - pathology ; Organometallic Compounds - chemistry ; Organometallic Compounds - pharmacology ; Ruthenium - chemistry ; Ruthenium - pharmacology ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - pathology ; Tumor Cells, Cultured ; Tumor Microenvironment - drug effects ; X-Ray Absorption Spectroscopy</subject><ispartof>Metallomics, 2016-08, Vol.8 (8), p.762-773</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-e64eaabfa2b806ba9c9c54052af66860a4c0ed50e94ec8370d2e20b49db90f4c3</citedby><cites>FETCH-LOGICAL-c378t-e64eaabfa2b806ba9c9c54052af66860a4c0ed50e94ec8370d2e20b49db90f4c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27460862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gransbury, Gemma K</creatorcontrib><creatorcontrib>Kappen, Peter</creatorcontrib><creatorcontrib>Glover, Chris J</creatorcontrib><creatorcontrib>Hughes, James N</creatorcontrib><creatorcontrib>Levina, Aviva</creatorcontrib><creatorcontrib>Lay, Peter A</creatorcontrib><creatorcontrib>Musgrave, Ian F</creatorcontrib><creatorcontrib>Harris, Hugh H</creatorcontrib><title>Comparison of KP1019 and NAMI-A in tumour-mimetic environments</title><title>Metallomics</title><addtitle>Metallomics</addtitle><description>NAMI-A and KP1019 are Ru
III
-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru
II
. The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 μm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively-coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru
III
to Ru
II
in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive.
Biotransformations of Ru(
iii
) anticancer drugs are compared under a range of controlled hypoxia levels provided by spheroids at different sizes.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Dimethyl Sulfoxide - analogs & derivatives</subject><subject>Dimethyl Sulfoxide - chemistry</subject><subject>Dimethyl Sulfoxide - pharmacology</subject><subject>Humans</subject><subject>Hypoxia - physiopathology</subject><subject>Indazoles - chemistry</subject><subject>Indazoles - pharmacology</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - pathology</subject><subject>Organometallic Compounds - chemistry</subject><subject>Organometallic Compounds - pharmacology</subject><subject>Ruthenium - chemistry</subject><subject>Ruthenium - pharmacology</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - pathology</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Microenvironment - drug effects</subject><subject>X-Ray Absorption Spectroscopy</subject><issn>1756-5901</issn><issn>1756-591X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0U1LxDAQBuAgiruuXrwrPYpQnbRJmlyEUvzCXfWwgreSplOobJo1aQX_vau7rldPMzAPA_MOIccULiik6tII2wNQxvUOGdOMi5gr-rq77YGOyEEIbwCCAfB9MkoyJkCKZEyuCmeX2rfBdZFroodnClRFuqujx3x2H-dR20X9YN3gY9ta7FsTYffRetdZ7PpwSPYavQh4tKkT8nJzPS_u4unT7X2RT2OTZrKPUTDUump0UkkQlVZGGc6AJ7oRQgrQzADWHFAxNDLNoE4wgYqpulLQMJNOyNl679K79wFDX9o2GFwsdIduCCWVlGcgUxD_oavTuUzoip6vqfEuBI9NufSt1f6zpFB-R1sWYjb_iTZf4dPN3qGyWG_pb5YrcLIGPpjt9O836Rd1cHux</recordid><startdate>20160801</startdate><enddate>20160801</enddate><creator>Gransbury, Gemma K</creator><creator>Kappen, Peter</creator><creator>Glover, Chris J</creator><creator>Hughes, James N</creator><creator>Levina, Aviva</creator><creator>Lay, Peter A</creator><creator>Musgrave, Ian F</creator><creator>Harris, Hugh H</creator><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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160801</creationdate><title>Comparison of KP1019 and NAMI-A in tumour-mimetic environments</title><author>Gransbury, Gemma K ; Kappen, Peter ; Glover, Chris J ; Hughes, James N ; Levina, Aviva ; Lay, Peter A ; Musgrave, Ian F ; Harris, Hugh H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-e64eaabfa2b806ba9c9c54052af66860a4c0ed50e94ec8370d2e20b49db90f4c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Dimethyl Sulfoxide - analogs & derivatives</topic><topic>Dimethyl Sulfoxide - chemistry</topic><topic>Dimethyl Sulfoxide - pharmacology</topic><topic>Humans</topic><topic>Hypoxia - physiopathology</topic><topic>Indazoles - chemistry</topic><topic>Indazoles - pharmacology</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - pathology</topic><topic>Organometallic Compounds - chemistry</topic><topic>Organometallic Compounds - pharmacology</topic><topic>Ruthenium - chemistry</topic><topic>Ruthenium - pharmacology</topic><topic>Spheroids, Cellular - drug effects</topic><topic>Spheroids, Cellular - pathology</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Microenvironment - drug effects</topic><topic>X-Ray Absorption Spectroscopy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gransbury, Gemma K</creatorcontrib><creatorcontrib>Kappen, Peter</creatorcontrib><creatorcontrib>Glover, Chris J</creatorcontrib><creatorcontrib>Hughes, James N</creatorcontrib><creatorcontrib>Levina, Aviva</creatorcontrib><creatorcontrib>Lay, Peter A</creatorcontrib><creatorcontrib>Musgrave, Ian F</creatorcontrib><creatorcontrib>Harris, Hugh H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Metallomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gransbury, Gemma K</au><au>Kappen, Peter</au><au>Glover, Chris J</au><au>Hughes, James N</au><au>Levina, Aviva</au><au>Lay, Peter A</au><au>Musgrave, Ian F</au><au>Harris, Hugh H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of KP1019 and NAMI-A in tumour-mimetic environments</atitle><jtitle>Metallomics</jtitle><addtitle>Metallomics</addtitle><date>2016-08-01</date><risdate>2016</risdate><volume>8</volume><issue>8</issue><spage>762</spage><epage>773</epage><pages>762-773</pages><issn>1756-5901</issn><eissn>1756-591X</eissn><abstract>NAMI-A and KP1019 are Ru
III
-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru
II
. The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 μm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively-coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru
III
to Ru
II
in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive.
Biotransformations of Ru(
iii
) anticancer drugs are compared under a range of controlled hypoxia levels provided by spheroids at different sizes.</abstract><cop>England</cop><pmid>27460862</pmid><doi>10.1039/c6mt00145a</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Metallomics, 2016-08, Vol.8 (8), p.762-773 |
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| language | eng |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Royal Society Of Chemistry Journals 2008- |
| subjects | Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Dimethyl Sulfoxide - analogs & derivatives Dimethyl Sulfoxide - chemistry Dimethyl Sulfoxide - pharmacology Humans Hypoxia - physiopathology Indazoles - chemistry Indazoles - pharmacology Neuroblastoma - drug therapy Neuroblastoma - pathology Organometallic Compounds - chemistry Organometallic Compounds - pharmacology Ruthenium - chemistry Ruthenium - pharmacology Spheroids, Cellular - drug effects Spheroids, Cellular - pathology Tumor Cells, Cultured Tumor Microenvironment - drug effects X-Ray Absorption Spectroscopy |
| title | Comparison of KP1019 and NAMI-A in tumour-mimetic environments |
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