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Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines

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Summary

Over the last few years a lot of research has been done to develop novel metal-based anti-cancer drugs, with the aim of improving clinical effectiveness, reducing general toxicity, and broadening the spectrum of activity. The search for novel metal-based antitumour drugs other than Pt agents includes the investigation of the cytotoxic activity of copper(I/II) compounds. Among these copper agents, particular attention has been recently devoted to hydrophilic copper(I) species bearing phosphines because of their noteworthy stability in aqueous media together with their remarkable in vitro cytotoxic activity. In this study we report on the synthesis, characterization and cytotoxic assays of a series of Cu(I) complexes with tris(2-cyanoethyl)phosphine (PCN) and bis(2-cyanoethyl)phenylphosphine (PCNPh). They were prepared by reaction of [Cu(CH3CN)4]+ or CuX2 precursors with the pertinent phosphine in acetone or acetonitrile solutions producing compounds of the following formulation: [Cu(PCN)2]+ 2, [Cu(CH3CN)(PCN)]+ 3, [Cu(X)(PCN)] (X = Cl, 4; Br, 5), and [Cu(PCNPh)2]+ 6. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumour cell lines. Cellular copper uptake rate was correlated with cell growth inhibition in 2008 human ovarian cancer cells. Moreover, copper(I)-PCN complexes were evaluated for their ability to alter the most relevant mitochondrial pathophysiological parameters such as respiration, coupling, ATP-synthetase activity and membrane potential in isolated mitochondria. These data were correlated with changes in mitochondrial membrane potential and production of reactive oxygen species (ROS) in drug-treated 2008 cells.

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Abbreviations

Cisplatin:

cis-diamminedichloroplatinum(II)

MTT:

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

RF:

resistance factor

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Acknowledgments

This work was financially supported by Ministero dell’Istruzione dell’Università e della Ricerca (PRIN 20078EWK9B). We are grateful to CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici). The authors thank A. Moresco for elemental analyses and Dr. Bolzati for HPLC measurements.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, 35131, Padova, Italy

    Alessandro Zanella, Valentina Gandin & Cristina Marzano

  2. ICIS- CNR, Corso Stati Uniti 4, 35127, Padova, Italy

    Marina Porchia, Fiorenzo Refosco & Francesco Tisato

  3. Dipartimento di Chimica Biologica, Università di Padova, viale Colombo 3, 35121, Padova, Italy

    Francesca Sorrentino, Guido Scutari & Maria Pia Rigobello

Authors
  1. Alessandro Zanella
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  2. Valentina Gandin
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  3. Marina Porchia
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  4. Fiorenzo Refosco
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  5. Francesco Tisato
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  6. Francesca Sorrentino
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  7. Guido Scutari
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  8. Maria Pia Rigobello
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  9. Cristina Marzano
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Corresponding author

Correspondence to Francesco Tisato.

Additional information

Zanella and Gandin contributed equally to this work.

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Zanella, A., Gandin, V., Porchia, M. et al. Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines. Invest New Drugs 29, 1213–1223 (2011). https://doi.org/10.1007/s10637-010-9466-7

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  • DOI: https://doi.org/10.1007/s10637-010-9466-7

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