Comparison of KP1019 and NAMI-A in tumour-mimetic environments

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dc.contributor.authorGransbury, G.
dc.contributor.authorKappen, P.
dc.contributor.authorGlover, C.
dc.contributor.authorHughes, J.
dc.contributor.authorLevina, A.
dc.contributor.authorLay, P.
dc.contributor.authorMusgrave, I.
dc.contributor.authorHarris, H.
dc.date.issued2016
dc.description.abstractNAMI-A and KP1019 are RuIII-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to RuII. 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 mm). 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 RuIII to RuII 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.
dc.description.statementofresponsibilityGemma K. Gransbury, Peter Kappen, Chris J. Glover, James N. Hughes, Aviva Levina, Peter A. Lay, Ian F. Musgravee and Hugh H. Harris
dc.identifier.citationMetallomics, 2016; 8(8):762-773
dc.identifier.doi10.1039/c6mt00145a
dc.identifier.issn1756-5901
dc.identifier.issn1756-591X
dc.identifier.orcidMusgrave, I. [0000-0003-1016-0588]
dc.identifier.orcidHarris, H. [0000-0002-3472-8628]
dc.identifier.urihttp://hdl.handle.net/2440/102464
dc.language.isoen
dc.publisherRoyal Society of Chemistry
dc.relation.granthttp://purl.org/au-research/grants/arc/DP140100176
dc.relation.granthttp://purl.org/au-research/grants/arc/DP130103566
dc.rightsThis journal is © The Royal Society of Chemistry 2016
dc.source.urihttps://doi.org/10.1039/c6mt00145a
dc.subjectSpheroids, Cellular
dc.subjectTumor Cells, Cultured
dc.subjectHumans
dc.subjectNeuroblastoma
dc.subjectRuthenium
dc.subjectRuthenium Compounds
dc.subjectOrganometallic Compounds
dc.subjectDimethyl Sulfoxide
dc.subjectIndazoles
dc.subjectAntineoplastic Agents
dc.subjectX-Ray Absorption Spectroscopy
dc.subjectTumor Microenvironment
dc.subjectHypoxia
dc.titleComparison of KP1019 and NAMI-A in tumour-mimetic environments
dc.typeJournal article
pubs.publication-statusPublished

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