Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex.
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.
Procházka
Lubomír
L
Veterinary Research Institute, Department of Immunology, Brno, Czech Republic.
Turánek
Jaroslav
J
Tesarík
Radek
R
Knotigová
Pavlína
P
Polásková
Pavlína
P
Andrysík
Zdenek
Z
Kozubík
Alois
A
Zák
Frantisek
F
Sova
Petr
P
Neuzil
Jiri
J
Machala
Miroslav
M
D000547:Amantadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects*; D057927:Hydrophobic and Hydrophilic Interactions; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D017671:Platinum Compounds / Q000737:chemistry*; D051381:Rats
D000970:Antineoplastic Agents; D018031:Connexin 43; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D000547:Amantadine; D002945:Cisplatin