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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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    Publication date
    2014-03-26
    Author
    van Rijt, S.H.
    Romero-Canelón, I.
    Fu, Y.
    Shnyder, Steven D.
    Sadler, P.J.
    Keyword
    Organometallic osmium compounds; Apoptosis; S-phase; Platinum drugs; Chemotherapeutics
    Rights
    © 2014 Royal Society of Chemistry. This is an Open Access article licensed under the Creative Commons CC-BY license.
    Peer-Reviewed
    Yes
    
    Metadata
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    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(Z6-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 mM). 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(Z6-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells pre-dominately 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 mito-chondrial 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.
    URI
    http://hdl.handle.net/10454/10063
    Version
    published version paper
    Citation
    Van Rijt SH, Romero-Canelón I, Fu Y, Shnyder SD and Sadler PJ (2014). Potent organometallic osmium compounds induce mitochondria-mediated apoptosis and S-phase cell cycle arrest in A549 non-small cell lung cancer cells. Metallomics. 6:1014-1022.
    Link to publisher’s version
    http://dx.doi.org/10.1039/c4mt00034j
    Type
    Article
    Collections
    Life Sciences Publications

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