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  • Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex

    Author(s)
    Prochazka, Lubomir
    Turanek, Jaroslav
    Tesarik, Radek
    Knotigova, Pavlina
    Polaskova, Pavlina
    Andrysik, Zdenek
    Kozubik, Alois
    Zak, Frantisek
    Sova, Petr
    Neuzil, Jiri
    Machala, Miroslav
    Griffith University Author(s)
    Neuzil, Jiri
    Year published
    2007
    Metadata
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    Abstract
    A new hydrophobic platinum(IV) complex, LA-12, a very efficient anticancer drug lacking cross-resistance with cisplatin (CDDP), is now being tested in clinical trials. Here we investigated the apoptogenic activity of LA-12 and its effect on gap-junctional intercellular communication (GJIC) in the rat liver epithelial cell line WB-F344. LA-12 induced apoptosis much more efficiently than did CDDP due to a combination of rapid penetration into the cell and attack on DNA, leading to fast activation of p53 and caspase-3. Exposure of WB-F344 cells to LA-12 led to rapid induction of the time- and dose-dependent decrease in GJIC. ...
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    A new hydrophobic platinum(IV) complex, LA-12, a very efficient anticancer drug lacking cross-resistance with cisplatin (CDDP), is now being tested in clinical trials. Here we investigated the apoptogenic activity of LA-12 and its effect on gap-junctional intercellular communication (GJIC) in the rat liver epithelial cell line WB-F344. LA-12 induced apoptosis much more efficiently than did CDDP due to a combination of rapid penetration into the cell and attack on DNA, leading to fast activation of p53 and caspase-3. Exposure of WB-F344 cells to LA-12 led to rapid induction of the time- and dose-dependent decrease in GJIC. On the molecular level, loss of GJIC induced by LA-12 was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated by the use of inhibitors of ERK activation. Inhibition of GJIC was linked to rapid hyperphosphorylation of connexin-43 and disappearance of connexon clusters from membranes, which was not observed in the case of CDDP.
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    Journal Title
    Archives of Biochemistry and Biophysics
    Volume
    462
    Issue
    1
    Publisher URI
    http://www.elsevier.com/wps/find/journaldescription.cws_home/622787/description#description
    DOI
    https://doi.org/10.1016/j.abb.2007.03.021
    Copyright Statement
    © 2007 Elsevier. Please refer to the journal's website for access to the definitive, published version.
    Subject
    Biochemistry and cell biology
    Publication URI
    http://hdl.handle.net/10072/18792
    Collection
    • Journal articles

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