Different cell cycle modulation following treatment of human ovarian carcinoma cells with a new platinum(IV) complex vs cisplatin

• Published in: Investigational new drugs Vol. 25; no. 5; pp. 435 - 443
• Main Authors: Horváth, Viktor, Soucek, Karel, Svihálková-Sindlerová, Lenka, Vondrácek, Jan, Blanárová, Olga, Hofmanová, Jirina, Sova, Petr, Kozubík, Alois
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.10.2007
• Subjects: Amantadine - analogs & derivatives; Amantadine - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; bcl-2-Associated X Protein - metabolism; Cancer therapies; Carcinoma - drug therapy; Carcinoma - metabolism; Cell cycle; Cell Cycle - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin - pharmacology; Clinical trials; Cyclin-dependent kinases; DNA damage; DNA repair; Drugs; Female; Humans; Kinases; Organoplatinum Compounds - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Pharmacology; Proteins; Proto-Oncogene Proteins c-mdm2 - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-007-9062-7

Platinum (IV) derivative with adamantylamine-LA-12-represents a new generation of highly efficient anti-cancer drug derived from cisplatin and is currently in the final stage of phase I clinical trials. Understanding the specific mechanisms of its effects on cell cycle is necessary for defining the mode of action of LA-12. In this study, we characterized the ability of LA-12 to induce cell cycle perturbations in ovarian cancer cell line A2780 as compared to equitoxic cisplatin treatment. LA-12 induced a permanent accumulation of A2780 cells in S phase while cisplatin caused G2/M arrest at 24-h time point, where we also detected an increased expression of Gadd45alpha protein. Although both derivatives induced a rapid increase of p53 expression, this was not associated with a down-regulation of Mdm2 protein. Increased expression of p21(Cip1/WAF1) protein and its association with cyclins A and B1 suggested that this cyclin-dependent kinase inhibitor might contribute significantly to the observed perturbations of cell cycle. The results of this study provide insight into the mechanism of action of platinum-based derivative with adamantylamine on cell cycle in ovarian cancer cells. The differences between effects of LA-12 and cisplatin suggest that more attention should be paid to elucidation of modes of action of novel platinum(IV) complexes at cellular level.