The novel platinum(IV) complex LA-12 induces p53 and p53/47 responses that differ from the related drug, cisplatin
Language English Country Great Britain, England Media print
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
18454047
DOI
10.1097/cad.0b013e3282f7f500
PII: 00001813-200804000-00005
Knihovny.cz E-resources
- MeSH
- Amantadine analogs & derivatives pharmacology MeSH
- Cell Cycle drug effects MeSH
- Drug Resistance, Neoplasm MeSH
- Cisplatin pharmacology MeSH
- Doxorubicin pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Protein p53 genetics metabolism MeSH
- Organoplatinum Compounds pharmacology MeSH
- Protein Processing, Post-Translational MeSH
- Cell Proliferation drug effects MeSH
- Protein Isoforms genetics metabolism MeSH
- Antineoplastic Agents pharmacology MeSH
- Flow Cytometry MeSH
- Oligonucleotide Array Sequence Analysis MeSH
- Signal Transduction MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Amantadine MeSH
- bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Browser
- Cisplatin MeSH
- Doxorubicin MeSH
- Tumor Suppressor Protein p53 MeSH
- Organoplatinum Compounds MeSH
- Protein Isoforms MeSH
- Antineoplastic Agents MeSH
The platinum(II)-based complex cisplatin is one of the most frequently used antitumour agents; however, a high incidence of harmful side effects and the frequent emergence of acquired resistance are the major clinical problems. The novel platinum(IV)-based complex LA-12 exhibits a high efficacy against cancer cell lines, including cisplatin-insensitive cells, but the mechanisms by which LA-12 perturbs cell growth are unclear. We tested the effects of LA-12 on the p53 response and demonstrate that LA-12 induces unique changes in the profile of gene expression compared with cisplatin and doxorubicin. Furthermore, the ability of LA-12 to disrupt cellular proliferation is greatly enhanced by the expression of p53 and p53/47 indicating both p53-dependent and p53-independent effects of LA-12. Exposure of the human cancer cell lines H1299, A2780, BT549 and BT474 to LA-12 alters the expression of p53 and p53/47 in both a time-dependent and dose-dependent manner. Treatment of cells with a low concentration of the drug results in accumulation of p53 and p53/47 concomitant with their posttranslational modification, whereas a high dose results in the disappearance of both the forms of p53. The distinct p53 activation profile of LA-12 compared with cisplatin and doxorubicin provides a molecular explanation for the ability of this drug to treat cisplatin-resistant cells and indicates its potential usefulness as an alternative antitumour agent in first-line therapy or as a second-line therapy in patients with acquired cisplatin resistance.
References provided by Crossref.org
The new platinum-based anticancer agent LA-12 induces retinol binding protein 4 in vivo
