The mitochondrial apoptotic pathway is induced by Cu(II) antineoplastic compounds (Casiopeínas®) in SK-N-SH neuroblastoma cells after short exposure times

The family of Copper(II) coordination compounds Casiopeínas ® ( Cas ) has shown antiproliferative activity in several tumour lines by oxidative cellular damage and mitochondrial dysfunction that lead to cell death through apoptotic pathways. The goal of this work is looking for the functional mechanism of CasIIgly , CasIIIia and CasIIIEa in neuroblastoma metastatic cell line SK-N-SH, a paediatric extra-cranial tumour which is refractory to several anti-carcinogenic agents. All Cas have shown higher antiproliferative activity than cisplatin (IC 50 = 123 μM) with IC 50 values of 18, 22 and 63 µM for CasIIgly , CasIIIEa and CasIIIia, respectively. At low concentrations and early times (4 h), these compounds cause a disruption of the mitochondrial transmembrane potential (Δψm). Concomitantly, an important depletion of intracellular glutathione and an increase of reactive oxygen species (ROS) hydrogen peroxide and radical superoxide were observed. On the other side, the lower cytotoxic effect of Casiopeínas on cultures of human peripheral blood lymphocytes (IC 50 CasIIgly = 1720 µM, IC 50 CasIIIEa = 3860 µM and IC 50 CasIIIia = 4700 µM) show the selectivity of these compounds over the tumour cells compared with the non-transformed cells. Chemically, glutathione (GSH) interacts with Casiopeínas ® through the coordination of sulphur atom to the metal centre, process which facilitates the electron transfer to get Cu(I), GSSG and the posterior production of ROS. Additionally, the molecular structure of CasIIIia as nitrate is reported. These results have shown that the anticarcinogenic activity of Casiopeínas ® on neuroblastoma SK-N-SH is through mitochondrial apoptosis due to the enhanced pro-oxidant environment promoted by the presence of the coordination copper compounds. Graphical Abstract