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Contrasting cellular uptake pathways for chlorido and iodido iminopyridine ruthenium arene anticancer complexes
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Romero-Canelón, Isolda, Pizarro, Ana M., Habtemariam, Abraha and Sadler, P. J. (2012) Contrasting cellular uptake pathways for chlorido and iodido iminopyridine ruthenium arene anticancer complexes. Metallomics, Volume 4 (Number 12). pp. 1271-1279. doi:10.1039/c2mt20189e ISSN 1756-5901.
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Official URL: http://dx.doi.org/10.1039/C2MT20189E
Abstract
The pathways involved in cellular uptake and accumulation of iminopyridine complexes of general formula [Ru(η6-p-cymene)(N,N-dimethyl-N′-[(E)-pyridine-2-ylmethylidene]benzene-1,4-diamine)X]PF6 bearing two different halido ligands X = Cl or I, have been explored. The ratio of passive/active cellular accumulation of Ru in A2780 human ovarian cancer cells is compared and contrasted with cisplatin. Also, saturation of cellular uptake, time-dependence of cellular influx/efflux equilibria, together with endocytotic pathways such as caveolae and facilitated diffusion are investigated and discussed. Temperature dependence studies of Ru accumulation in the A2780 cells show that in contrast to cisplatin (CDDP) and chlorido complex 1, which are taken up largely through active transport, the iodido complex 2 enters cells via passive transport. The cellular efflux of Ru is slow (ca. 25% retained after 72 h) and is partially inhibited by verapamil, implicating the P-gp protein in the efflux mechanism. Ouabain inhibition experiments suggest that the cellular uptake of these ruthenium complexes relies at least in part on facilitated diffusion, and in particular is dependent on the membrane potential. In addition the finding that depletion of cellular ATP with antimycin A had little effect on cellular Ru accumulation from iodido complex 2 is consistent with passive diffusion. In contrast, ATP depletion caused a major increase in cellular accumulation of ruthenium from chlorido complex 1.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Metal complexes -- Therapeutic use, Metal complexes -- Physiological transport, Ruthenium -- Therapeutic use, Aromatic compounds -- Therapeutic use, Ruthenium -- Physiological transport, Aromatic compounds -- Physiological transport, Complex compounds, Cancer -- Treatment | ||||
Journal or Publication Title: | Metallomics | ||||
Publisher: | Royal Society of Chemistry | ||||
ISSN: | 1756-5901 | ||||
Official Date: | 2012 | ||||
Dates: |
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Volume: | Volume 4 | ||||
Number: | Number 12 | ||||
Page Range: | pp. 1271-1279 | ||||
DOI: | 10.1039/c2mt20189e | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Date of first compliant deposit: | 24 December 2015 | ||||
Date of first compliant Open Access: | 24 December 2015 | ||||
Funder: | European Research Council (ERC), European Regional Development Fund (ERDF), Advantage West Midlands (AWM), Universidad de los Andes (Mérida, Venezuela), University of Warwick | ||||
Grant number: | 24363 (ERC) |
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