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

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Summary

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 Gadd45α 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 p21Cip1/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.

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Abbreviations

cis-DDP:

cis-diamminedichloroplatinum(II)

LA-12:

(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)

JM216 (satraplatin):

(OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum(IV)

Cisplatin (50), LA-12 (50):

IC50 drug concentrations inhibiting cell proliferation by 50%

Pt(II):

planar and four coordinate platinum complex

Pt(IV):

octahedral and six coordinate platinum complex

DMSO:

dimethyl sulfoxide

PI:

propidium iodide

BrdU:

(5-bromo-2′-deoxyuridine)

HRP:

horseradish peroxidase

PBS:

phosphate buffered saline

SDS:

sodium dodecyl sulphate

PAGE:

polyacrylamide gel electrophoresis

HPLC:

high performance liquid chromatography

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Acknowledgments

This work was supported by grant No. 301/07/1557 of the Czech Science Foundation and by the Academy of Sciences of the Czech Republic (grant No. 1QS500040507 and Research Plan AVOZ50040507). The authors wish to thank Jaromíra Netíková, Eva Lincová, Zuzana Koubková, and Lenka Kočí for superb technical assistance; Bořivoj Vojtěšek (Masaryk Memorial Cancer Institute, Brno) for providing p53 antibody; and Ladislav Červený for correction of English.

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Authors and Affiliations

  1. Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, CZ-612 65, Brno, Czech Republic

    Viktor Horváth, Karel Souček, Lenka Švihálková-Šindlerová, Jan Vondráček, Olga Blanářová, Jiřina Hofmanová & Alois Kozubík

  2. R&D, PLIVA-Lachema a.s., Karásek 1, CZ-621 33, Brno, Czech Republic

    Petr Sova

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  1. Viktor Horváth
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Correspondence to Alois Kozubík.

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Horváth, V., Souček, K., Švihálková-Šindlerová, L. et al. Different cell cycle modulation following treatment of human ovarian carcinoma cells with a new platinum(IV) complex vs cisplatin. Invest New Drugs 25, 435–443 (2007). https://doi.org/10.1007/s10637-007-9062-7

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