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Cisplatin handover between copper transporters: the effect of reducing agents

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Abstract

Copper (Cu) transporters emerged as key factors at the basis of the biological response to antitumor platinum (Pt) drugs, which are among the most potent and broadly used chemotherapeutics. ATP7A and ATP7B (the Menkes and Wilson disease proteins, respectively) appear to be implicated in promoting tumor cell resistance to cisplatin. Cu-ATPases could bind the drug and, with the alleged involvement of the chaperone ATOX1, contribute to cell detoxification and survival. Here, we report the spectroscopic characterization of cisplatin binding to ATOX1 and MNK1, the first metal-binding domain of ATP7A, in the presence of the physiological reducing agent glutathione, a sulfur-containing molecule responsible for the majority of Pt detoxification in the cytosol. Under conditions mimicking the cellular environment, we show that cisplatin transfer from ATOX1 to MNK1 does not occur at a detectable rate. These results appear to contradict other literature data which, however, were obtained in the presence of exogenous reducing agents such as tris(2-carboxyethyl)phosphine (TCEP) having good coordinating ability for soft metal ions (such as Pt) and strong trans-labilizing effect. A better understanding of Pt drug processing by Cu trafficking proteins under physiological conditions may help to answer key issues, such as drug availability in tumor cells and resistance.

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Abbreviations

MBD:

Metal-binding domain

GSH:

Glutathione

TCEP:

Tris(2-carboxyethyl)phosphine

DTT:

Dithiothreitol

NMR:

Nuclear magnetic resonance

ESI–MS:

Electrospray ionization mass spectrometry

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Acknowledgments

We are grateful to the University of Bari “Aldo Moro”, the Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB), the Italian Ministero dell’Università e della Ricerca (MIUR, PON 01078), and the European Commission (COST Action CM1105) for funding and support.

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Authors and Affiliations

  1. Department of Chemistry, University of Bari “Aldo Moro”, via E. Orabona 4, 70125, Bari, Italy

    Angela Galliani, Maurizio Losacco, Alessia Lasorsa, Giovanni Natile & Fabio Arnesano

Authors
  1. Angela Galliani
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  2. Maurizio Losacco
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  3. Alessia Lasorsa
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  4. Giovanni Natile
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  5. Fabio Arnesano
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Corresponding authors

Correspondence to Giovanni Natile or Fabio Arnesano.

Additional information

Responsible Editors: Lucia Banci and Claudio Luchinat.

This paper is dedicated to the memory of Ivano Bertini (1940–2012).

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Galliani, A., Losacco, M., Lasorsa, A. et al. Cisplatin handover between copper transporters: the effect of reducing agents. J Biol Inorg Chem 19, 705–714 (2014). https://doi.org/10.1007/s00775-014-1138-1

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  • DOI: https://doi.org/10.1007/s00775-014-1138-1

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