The mitochondrial apoptotic pathway is induced by Cu(II) antineoplastic compounds (Casiopeínas®) in SK-N-SH neuroblastoma cells after short exposure times
Por:
Carlos Garcia-Ramos, Juan, Grizett Gutierrez, Anllely, Vazquez-Aguirre, Adriana, Toledano-Magana, Yanis, Luisa Alonso-Saenz, Ana, Gomez-Vidales, Virginia, Flores-Alamo, Marcos, Mejia, Carmen, Ruiz-Azuara, Lena
Publicada:
1 feb 2017
Resumen:
Abstract: 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 (IC50 = 123 µM) with IC50 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 ( ?m). 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 (IC50 CasIIgly = 1720 µM, IC50 CasIIIEa = 3860 µM and IC50 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: [Figure not available: see fulltext.] © 2016, Springer Science+Business Media New York.
Filiaciones:
Univ Nacl Autonoma Mexico, Fac Quim, Lab Quim Inorgan Med, Ave Univ 3000, Mexico City 04510, DF, Mexico
Univ Nacl Autonoma Mexico, Inst Quim, Ave Univ 3000, Mexico City 04510, DF, Mexico
Univ Veracruzana, Ctr Invest Biomed, Jalapa, Veracruz, Mexico
Univ Autonoma Queretaro, Fac Ciencias Nat, Ave Ciencias S-N Juriquilla, Delegacion Santa Rosa Ja 76230, Queretaro, Mexico
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