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

Autor:	Guido Cavaletti, Gabriella Nicolini, Carlo Santini, Alberto Bravin, S. Semperboni, M Monfrini, Maura Pellei, Cecilia Ceresa, Valentina Gandin, F Avezza, Paola Alberti
Přispěvatelé:	Ceresa, C, Nicolini, G, Semperboni, S, Gandin, V, Monfrini, M, Avezza, F, Alberti, P, Bravin, A, Pellei, M, Santini, C, Cavaletti, G
Rok vydání:	2018
Předmět:	Chemotherapy Metal-based drug Neurotoxicity Phosphane complexes Neuroscience (all) Toxicology 0301 basic medicine Tris 03 medical and health sciences chemistry.chemical_compound In vivo Neurotoxiciy Chemotherapy Metal-based drug phosphane cpmplexes medicine IC50 Cisplatin Chemistry General Neuroscience medicine.disease Molecular biology In vitro 030104 developmental biology Proteasome Cancer cell Phosphane complexe medicine.drug
Zdroj:	Neurotoxicity Research. 34:93-108
ISSN:	1476-3524 1029-8428
Popis:	[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.
Databáze:	OpenAIRE
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