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Potent organometallic osmium compounds induce mitochondria-mediated apoptosis and S-phase cell cycle arrest in A549 non-small cell lung cancer cells
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Rijt, Sabine H. van, Romero-Canelón, Isolda, Fu, Ying, Shnyder, Steve D. and Sadler, P. J. (2014) Potent organometallic osmium compounds induce mitochondria-mediated apoptosis and S-phase cell cycle arrest in A549 non-small cell lung cancer cells. Metallomics, 6 (5). pp. 1014-1022. doi:10.1039/c4mt00034j ISSN 1756-5901.
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Official URL: http://dx.doi.org/10.1039/C4MT00034J
Abstract
The problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands, [Os(η6-arene)(p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 μM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their log P values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(η6-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells predominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mitochondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics.
Item Type: | Journal Article | ||||||||||
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Subjects: | Q Science > QD Chemistry | ||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||
Library of Congress Subject Headings (LCSH): | Antineoplastic agents -- Design, Osmium, Organometallic compounds -- Physiological effect, Lungs -- Cancer -- Treatment -- Research | ||||||||||
Journal or Publication Title: | Metallomics | ||||||||||
Publisher: | Royal Society of Chemistry | ||||||||||
ISSN: | 1756-5901 | ||||||||||
Official Date: | 1 May 2014 | ||||||||||
Dates: |
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Volume: | 6 | ||||||||||
Number: | 5 | ||||||||||
Number of Pages: | 9 | ||||||||||
Page Range: | pp. 1014-1022 | ||||||||||
DOI: | 10.1039/c4mt00034j | ||||||||||
Status: | Peer Reviewed | ||||||||||
Publication Status: | Published | ||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||
Date of first compliant deposit: | 30 December 2015 | ||||||||||
Date of first compliant Open Access: | 30 December 2015 | ||||||||||
Funder: | Engineering and Physical Sciences Research Council (EPSRC), European Research Council (ERC), University of Warwick. Institute of Advanced Study (IAS), Birmingham Science City, Advantage West Midlands (AWM), European Regional Development Fund (ERDF) | ||||||||||
Grant number: | EP/H500308/1 (EPSRC), 247450 (ERC), |
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