Neurotoxicity Research

, Volume 34, Issue 1, pp 93–108 | Cite as

Evaluation of the Profile and Mechanism of Neurotoxicity of Water-Soluble [Cu(P)4]PF6 and [Au(P)4]PF6 (P = thp or PTA) Anticancer Complexes

  • C. Ceresa
  • G. Nicolini
  • S. Semperboni
  • V. Gandin
  • M. Monfrini
  • F. Avezza
  • P. Alberti
  • A. Bravin
  • M. Pellei
  • C. Santini
  • Guido Cavaletti
ORIGINAL ARTICLE
  • 141 Downloads

Abstract

[Cu(thp)4]PF6, [Cu(PTA)4]PF6, [Au(thp)4]PF6 and [Au(PTA)4]PF6 are phosphane (thp = tris(hydroxymethyl)phosphane; PTA = 1,3,5-triaza-7-phosphaadamantane) copper(I) and gold(I) water-soluble complexes characterized by high anticancer activity in a wide range of solid tumors, often able to overcome drug resistance of platinum-based compounds. For these reasons, they have been proposed as a valid alternative to platinum-based chemotherapeutic drugs (e.g., cisplatin and oxaliplatin). In vitro experiments performed on organotypic cultures of dorsal root ganglia (DRG) from 15-day-old rat embryos revealed that copper-based compounds were not neurotoxic even at concentrations higher than the IC50 obtained in human cancer cells while [Au(PTA)4]PF6 was neurotoxic at lower concentration than IC50 in cancer cell lines. The ability of these compounds to hinder the proteasome machinery in DRG neurons was tested by fluorimetric assay showing that the non-neurotoxic copper-based complexes do not inhibit proteasome activity in DRG primary neuron cultures. On the contrary, the neurotoxic complex [Au(PTA)4]PF6, induced a significant inhibition of proteasome activity even at concentrations lower than the IC50 in cancer cells. The proteasome inhibition induced by [Au(PTA)4]PF6 was associated with a significant increase in α-tubulin polymerization that was not observed following the treatment with copper-based compounds. Uptake experiments performed by atomic absorption spectrometry showed that both copper-based complexes and [Au(PTA)4]PF6 are internalized in neuron cultures. In vitro and in vivo preliminary data confirmed copper-based complexes as the most promising compounds, not only for their anticancer activity but also concerning the peripheral neurotoxicity profile.

Keywords

Neurotoxicity Chemotherapy Metal-based drug Phosphane complexes 

Notes

Acknowledgments

This study was supported by a grant from Associazione Italiana Ricerca sul Cancro (AIRC, Progetto IG 2016 Id.18631, PI Guido Cavaletti). The authors thank the COST action TD1205 “Innovative methods in radiotherapy and radiosurgery using synchrotron radiation” for the support given in the preparation of the manuscript.

Compliance with Ethical Standards

This study was supported by a grant from Associazione Italiana Ricerca sul Cancro (AIRC, Progetto IG 2016 Id.18631, PI Guido Cavaletti).

Authors Gandin V., Pellei M., and Santini C. have the Patent WO2013/024324 for the [Cu(thp)4]PF6 compound used in this study.

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

12640_2018_9864_MOESM1_ESM.pdf (209 kb)
ESM 1 (PDF 209 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • C. Ceresa
    • 1
  • G. Nicolini
    • 1
  • S. Semperboni
    • 1
    • 2
  • V. Gandin
    • 3
  • M. Monfrini
    • 1
  • F. Avezza
    • 1
  • P. Alberti
    • 1
    • 2
  • A. Bravin
    • 4
  • M. Pellei
    • 5
  • C. Santini
    • 5
  • Guido Cavaletti
    • 1
  1. 1.Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and SurgeryUniversity of Milano-BicoccaMonzaItaly
  2. 2.PhD Program in NeuroscienceUniversity of Milano-BicoccaMonzaItaly
  3. 3.Department of Pharmaceutical and Pharmacological SciencesUniversity of PadovaPadovaItaly
  4. 4.ID17, European Synchrotron Radiation FacilityGrenobleFrance
  5. 5.School of Science and Technology - Chemistry DivisionUniversity of CamerinoCamerinoItaly

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