Evaluation of the Profile and Mechanism of Neurotoxicity of Water-Soluble [Cu(P) 4 ]PF 6 and [Au(P) 4 ]PF 6 (P = thp or PTA) Anticancer Complexes.

Autor: Ceresa C; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy., Nicolini G; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy., Semperboni S; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy.; PhD Program in Neuroscience, University of Milano-Bicocca, Monza, Italy., Gandin V; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy., Monfrini M; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy., Avezza F; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy., Alberti P; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy.; PhD Program in Neuroscience, University of Milano-Bicocca, Monza, Italy., Bravin A; ID17, European Synchrotron Radiation Facility, Grenoble, France., Pellei M; School of Science and Technology - Chemistry Division, University of Camerino, Camerino, Italy., Santini C; School of Science and Technology - Chemistry Division, University of Camerino, Camerino, Italy., Cavaletti G; Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900, Monza, MB, Italy. guido.cavaletti@unimib.it.
Jazyk: angličtina
Zdroj: Neurotoxicity research [Neurotox Res] 2018 Jul; Vol. 34 (1), pp. 93-108. Date of Electronic Publication: 2018 Jan 17.
DOI: 10.1007/s12640-018-9864-8
Abstrakt: [Cu(thp) 4 ]PF 6 , [Cu(PTA) 4 ]PF 6 , [Au(thp) 4 ]PF 6 and [Au(PTA) 4 ]PF 6 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 IC 50 obtained in human cancer cells while [Au(PTA) 4 ]PF 6 was neurotoxic at lower concentration than IC 50 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 ]PF 6 , induced a significant inhibition of proteasome activity even at concentrations lower than the IC 50 in cancer cells. The proteasome inhibition induced by [Au(PTA) 4 ]PF 6 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 ]PF 6 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.
Databáze: MEDLINE
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