The novel platinum(IV) complex LA-12 induces p53 and p53/47 responses that differ from the related drug, cisplatin.
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.
Hrstka
Roman
R
Masaryk Memorial Cancer Institute, PLIVA-Lachema, Brno, Czech Republic.
Powell
Darren J
DJ
Kvardova
Veronika
V
Roubalova
Eva
E
Bourougaa
Karima
K
Candeias
Marco M
MM
Sova
Petr
P
Zak
Frantisek
F
Fåhraeus
Robin
R
Vojtĕsek
Borivoj
B
D000547:Amantadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D004317:Doxorubicin; D000547:Amantadine; D002945:Cisplatin