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Contribution of intracellular ATP to cisplatin resistance of tumor cells

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Abstract

Decreased cellular accumulation of cisplatin is a frequently observed mechanism of resistance to the drug. Beside passive diffusion, several cellular proteins using ATP hydrolysis as an energy source are assumed to be involved in cisplatin transport in and out of the cell. This investigation aimed at clarifying the contribution of intracellular ATP as an indicator of energy-dependent transport to cisplatin resistance using the A2780 human ovarian adenocarcinoma cell line and its cisplatin-resistant variant A2780cis. Depletion of intracellular ATP with oligomycin significantly decreased cellular platinum accumulation (measured by flameless atomic absorption spectrometry) in sensitive but not in resistant cells, and did not affect cisplatin efflux in both cell lines. Inhibition of Na+,K+-ATPase with ouabain reduced platinum accumulation in A2780 cells but to a lesser extent compared with oligomycin. Western blot analysis revealed lower expression of Na+,K+-ATPase α1 subunit in resistant cells compared with sensitive counterparts. The basal intracellular ATP level (determined using a bioluminescence-based assay) was significantly higher in A2780cis cells than in A2780 cells. Our results highlight the importance of ATP-dependent transport, among other processes mediated by Na+,K+-ATPase, for cisplatin influx in sensitive cells. Cellular platinum accumulation in resistant cells is reduced and less dependent on energy sources, which may partly result from Na+,K+-ATPase downregulation. Our data suggest the involvement of other ATP-dependent processes beside those regulated by Na+,K+-ATPase. Higher basal ATP level in cisplatin-resistant cells, which appears to be a consequence of enhanced mitochondrial ATP production, may represent a survival mechanism established during development of resistance.

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Abbreviations

ATP:

Adenosine 5′-triphosphate

ATP7A:

ATPase, copper transporting, alfa polypeptide

ATP7B:

ATPase, copper transporting, beta polypeptide

BCA:

Bicinchoninic acid

BSA:

Bovine serum albumin

CTR1:

Copper transporter 1

CTR2:

Copper transporter 2

DAPI:

4′,6-diamidino-2-phenylindole

DMSO:

Dimethylsulfoxide

EDTA:

Ethylenediaminetetraacetic acid

ETC:

Electron transport chain

MRP:

Multidrug resistance-associated protein

MTP:

Mitochondrial transmembrane potential

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OCT2:

Organic cation transporter 2

PBS:

Phosphate buffered saline

ROS:

Reactive oxygen species

SDS:

Sodium dodecyl sulfate

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Acknowledgments

The authors would like to thank the working groups of Michael Wiese (Pharmaceutical Chemistry II, University of Bonn) and Michael Famulok (Chemical Biology, University of Bonn) for their support.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany

    Michaela L. Krieger & Gerd Bendas

  2. Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany

    Verena Schneider, Ulrich Jaehde & Ganna V. Kalayda

Authors
  1. Verena Schneider
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  2. Michaela L. Krieger
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  3. Gerd Bendas
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  4. Ulrich Jaehde
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  5. Ganna V. Kalayda
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Correspondence to Ganna V. Kalayda.

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Schneider, V., Krieger, M.L., Bendas, G. et al. Contribution of intracellular ATP to cisplatin resistance of tumor cells. J Biol Inorg Chem 18, 165–174 (2013). https://doi.org/10.1007/s00775-012-0960-6

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