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The novel platinum(IV) complex LA-12 induces p53 and p53/47 responses that differ from the related drug, cisplatin

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HRSTKA Roman POWELL Darren J KVARDOVA Veronika ROUBALOVÁ Eva BOUROUGAA Karima CANDEIAS Marco M SOVA Petr ZAK Frantisek FAHRAEUS Robin VOJTĚŠEK Bořivoj

Rok publikování 2008
Druh Článek v odborném periodiku
Časopis / Zdroj ANTI-CANCER DRUGS
Citace
Klíčová slova cisplatin; LA-12; p53; p53/47
Popis The platinum(II)-based complex cisplatin is one of the most frequently used antiturnour 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. Anti-Cancer Drugs 19:369-379 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

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