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Activation of P-glycoprotein (Pgp)-mediated drug efflux by extracellular acidosis: in vivo imaging with 68Ga-labelled PET tracer

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

In vitro it has been shown that the functional activity of P-glycoprotein (Pgp), an important drug transporter responsible for multidrug resistance, can be strongly increased by extracellular acidosis. Here mitogen-activated protein kinases (MAPK) (p38, ERK1/2) seem to play an important role for signal transduction. However, it is unclear whether these effects are also relevant in vivo.

Methods

With the newly developed PET tracer Schiff base-based 68Ga-MFL6.MZ the functional Pgp activity was visualized under acidic conditions and during inhibition of MAPKs non-invasively by means of microPET in rat tumours. Tumours were acidified either by inspiratory hypoxia (8% O2) or by injection of lactic acid. Inhibitors of the MAPK were injected intratumourally.

Results

With increasing tumour volume the tumour pH changed from 7.0 to 6.7 and simultaneously the Pgp activity increased almost linearly. When the tumour was acidified by direct lactic acid injection the PET tracer uptake was reduced by 20% indicating a higher transport rate out of the cells. Changing the inspiratory O2 fraction to 8% dynamically led to a reduction of extracellular pH and in parallel to a decrease of tracer concentration. While inhibition of the p38 pathway reduced the Pgp transport rate, inhibition of ERK1/2 had practically no impact.

Conclusion

An acidic extracellular environment significantly stimulates the Pgp activity. The p38 MAPK pathway plays an important role for Pgp regulation in vivo, whereas ERK1/2 is of minor importance. From these results new strategies for overcoming multidrug resistance (e.g. reducing tumour acidosis, inhibition of p38) may be developed.

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Abbreviations

Pgp:

P-glycoprotein

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Acknowledgments

The study was supported by Deutsche Krebshilfe (grant 109136).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Institute of Physiology and Pathophysiology, University Medicine Mainz, Duesbergweg 6, 55099, Mainz, Germany

    Oliver Thews & Wolfgang Dillenburg

  2. Institute of Nuclear Chemistry, University of Mainz, 55099, Mainz, Germany

    Marco Fellner & Frank Rösch

  3. Department of Nuclear Medicine, University Medicine Mainz, 55101, Mainz, Germany

    Hans-Georg Buchholz, Nicole Bausbacher & Mathias Schreckenberger

Authors
  1. Oliver Thews
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  2. Wolfgang Dillenburg
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  3. Marco Fellner
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  4. Hans-Georg Buchholz
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  5. Nicole Bausbacher
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  6. Mathias Schreckenberger
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  7. Frank Rösch
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Corresponding author

Correspondence to Oliver Thews.

Additional information

Part of this study forms the doctoral theses of W. Dillenburg and M. Fellner.

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Thews, O., Dillenburg, W., Fellner, M. et al. Activation of P-glycoprotein (Pgp)-mediated drug efflux by extracellular acidosis: in vivo imaging with 68Ga-labelled PET tracer. Eur J Nucl Med Mol Imaging 37, 1935–1942 (2010). https://doi.org/10.1007/s00259-010-1504-3

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  • DOI: https://doi.org/10.1007/s00259-010-1504-3

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