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Comparison of KP1019 and NAMI-A in tumour-mimetic environments.
Metallomics. 2016 08 01; 8(8):762-73.M

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.

Authors+Show Affiliations

Department of Chemistry, The University of Adelaide, SA 5005, Australia. hugh.harris@adelaide.edu.au.Australian Synchrotron, Clayton, VIC 3168, Australia.Australian Synchrotron, Clayton, VIC 3168, Australia.Department of Molecular and Cellular Biology, The University of Adelaide, SA 5005, Australia.School of Chemistry, The University of Sydney, NSW 2006, Australia.School of Chemistry, The University of Sydney, NSW 2006, Australia.School of Medical Sciences, The University of Adelaide, SA 5005, Australia.Department of Chemistry, The University of Adelaide, SA 5005, Australia. hugh.harris@adelaide.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27460862

Citation

Gransbury, Gemma K., et al. "Comparison of KP1019 and NAMI-A in Tumour-mimetic Environments." Metallomics : Integrated Biometal Science, vol. 8, no. 8, 2016, pp. 762-73.
Gransbury GK, Kappen P, Glover CJ, et al. Comparison of KP1019 and NAMI-A in tumour-mimetic environments. Metallomics. 2016;8(8):762-73.
Gransbury, G. K., Kappen, P., Glover, C. J., Hughes, J. N., Levina, A., Lay, P. A., Musgrave, I. F., & Harris, H. H. (2016). Comparison of KP1019 and NAMI-A in tumour-mimetic environments. Metallomics : Integrated Biometal Science, 8(8), 762-73. https://doi.org/10.1039/c6mt00145a
Gransbury GK, et al. Comparison of KP1019 and NAMI-A in Tumour-mimetic Environments. Metallomics. 2016 08 1;8(8):762-73. PubMed PMID: 27460862.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of KP1019 and NAMI-A in tumour-mimetic environments. AU - Gransbury,Gemma K, AU - Kappen,Peter, AU - Glover,Chris J, AU - Hughes,James N, AU - Levina,Aviva, AU - Lay,Peter A, AU - Musgrave,Ian F, AU - Harris,Hugh H, PY - 2016/7/28/entrez PY - 2016/7/28/pubmed PY - 2017/11/29/medline SP - 762 EP - 73 JF - Metallomics : integrated biometal science JO - Metallomics VL - 8 IS - 8 N2 - 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. SN - 1756-591X UR - https://www.unboundmedicine.com/medline/citation/27460862/Comparison_of_KP1019_and_NAMI_A_in_tumour_mimetic_environments_ L2 - https://doi.org/10.1039/c6mt00145a DB - PRIME DP - Unbound Medicine ER -