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

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Prochazka, Lubomir
Turanek, Jaroslav
Tesarik, Radek
Knotigova, Pavlina
Polaskova, Pavlina
Andrysik, Zdenek
Kozubik, Alois
Zak, Frantisek
Sova, Petr
Neuzil, Jiri
Machala, Miroslav
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2007
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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. 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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Archives of Biochemistry and Biophysics

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462

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1

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© 2007 Elsevier. Please refer to the journal's website for access to the definitive, published version.

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Biochemistry and cell biology

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