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Dinuclear platinum complexes with N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells: new insights into the mechanism of resistance

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Abstract

The cellular processing of three fluorescent N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl=2-aminoethyl, 3-aminoprop-1-yl or 4-aminobut-1-yl) and their dinuclear platinum complexes in A2780 human ovarian carcinoma cells with acquired resistance to cisplatin has been monitored over time by time-lapse fluorescence microscopy. The results were compared with the previously reported observations in the parent A2780 cell line. The cellular distribution pattern for the free ligands is similar in sensitive and resistant cells, whereas significant differences in cellular distribution were observed in the case of the platinum complexes. In the cisplatin-resistant cell line the platinum complexes were found to be sequestrated in acidic vesicles in the cytosol from the very beginning of the incubation. This sequestration was not observed in the case of sensitive cells. Platinum accumulation in vesicles possibly presents a mechanism of resistance to platinum complexes. This mechanism appears to be unrelated to the mechanism of deactivation of platinum compounds by glutathione. Encapsulation of the dinuclear platinum complexes in lysosomal vesicles provides a plausible explanation for the decreased activity of these compounds in the resistant cell line, as compared to the sensitive cell line.

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Fig. 9 A–D

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Abbreviations

AQ2:

N,N′-bis(2-aminoethyl)-1,4-diaminoanthracene-9,10-dione

AQ3:

N,N′-bis(3-aminoprop-1-yl)-1,4-diaminoanthracene-9,10-dione

AQ4:

N,N′-bis(4-aminobut-1-yl)-1,4-diaminoanthracene-9,10-dione

l-BSO:

l-buthionine-S,R-sulfoximine

dien:

diethylenetriamine

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide

PAQ2:

[{trans-PtCl(NH3)2}2(μ-AQ2)](NO3)2

PAQ3:

[{trans-PtCl(NH3)2}2(μ-AQ3)](NO3)2

PAQ4:

[{trans-PtCl(NH3)2}2(μ-AQ4)](NO3)2

PAM:

[{Pt(dien)}2(μ-AQ2)](NO3)4

PBS:

phosphate buffered saline

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Acknowledgements

The authors wish to thank Johnson Matthey (Reading, UK) for a generous gift of K2PtCl4. Also the support and sponsorship by COST Actions D20/0001/00, D20/0002/00 and D20/003/01 (biocoordination chemistry) is kindly acknowledged. This work has been performed under auspices of the joint BIOMAC Research Graduate School of Leiden University and Delft University of Technology.

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Authors and Affiliations

  1. Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA , Leiden, The Netherlands

    Ganna V. Kalayda, Bart A. J. Jansen, Peter Wielaard & Jan Reedijk

  2. Laboratory for Cytochemistry and Cytometry, Department of Molecular Cell Biology, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL , Leiden, The Netherlands

    Chris Molenaar & Hans J. Tanke

Authors
  1. Ganna V. Kalayda
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  2. Bart A. J. Jansen
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  3. Chris Molenaar
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  4. Peter Wielaard
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  5. Hans J. Tanke
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  6. Jan Reedijk
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Correspondence to Jan Reedijk.

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Kalayda, G.V., Jansen, B.A.J., Molenaar, C. et al. Dinuclear platinum complexes with N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells: new insights into the mechanism of resistance. J Biol Inorg Chem 9, 414–422 (2004). https://doi.org/10.1007/s00775-004-0540-5

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  • DOI: https://doi.org/10.1007/s00775-004-0540-5

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