Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
17466256
DOI
10.1016/j.abb.2007.03.021
PII: S0003-9861(07)00150-6
Knihovny.cz E-resources
- MeSH
- Amantadine analogs & derivatives pharmacology MeSH
- Apoptosis * MeSH
- Cell Line MeSH
- Cisplatin pharmacology MeSH
- Epithelial Cells metabolism MeSH
- Phosphorylation MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Connexin 43 metabolism MeSH
- Rats MeSH
- Gap Junctions drug effects MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds pharmacology MeSH
- Antineoplastic Agents pharmacology MeSH
- Platinum Compounds chemistry MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amantadine MeSH
- bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Browser
- Cisplatin MeSH
- Connexin 43 MeSH
- Organoplatinum Compounds MeSH
- Antineoplastic Agents MeSH
- Platinum Compounds MeSH
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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