Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma
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Renata Colla1, Alberto Izzotti2,3, Chiara De Ciucis1, Daniela Fenoglio4, Silvia Ravera5, Andrea Speciale1, Roberta Ricciarelli1, Anna Lisa Furfaro6, Alessandra Pulliero2, Mario Passalacqua1, Nicola Traverso1, Maria Adelaide Pronzato1, Cinzia Domenicotti1, Barbara Marengo1
1Department of Experimental Medicine, University of Genova, Genova, Italy
2Department of Health Sciences, University of Genova, Genova, Italy
3IRCCS AOU San Martino IST Genova, Genova, Italy
4Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genova, Genova, Italy
5Department of Pharmacy, University of Genova, Genova, Italy
6Giannina Gaslini Institute, Genova, Italy
Barbara Marengo, email: Barbara.Marengo@unige.it
Keywords: neuroblastoma, multi-drug resistance, glutathione, antioxidants, aerobic metabolism
Received: March 18, 2016 Accepted: September 13, 2016 Published: September 23, 2016
Neuroblastoma, a paediatric malignant tumor, is initially sensitive to etoposide, a drug to which many patients develop chemoresistance. In order to investigate the molecular mechanisms responsible for etoposide chemoresistance, HTLA-230, a human MYCN-amplified neuroblastoma cell line, was chronically treated with etoposide at a concentration that in vitro mimics the clinically-used dose. The selected cells (HTLA-Chr) acquire multi-drug resistance (MDR), becoming less sensitive than parental cells to high doses of etoposide or doxorubicin. MDR is due to several mechanisms that together contribute to maintaining non-toxic levels of H2O2. In fact, HTLA-Chr cells, while having an efficient aerobic metabolism, are also characterized by an up-regulation of catalase activity and higher levels of reduced glutathione (GSH), a thiol antioxidant compound. The combination of such mechanisms contributes to prevent membrane lipoperoxidation and cell death. Treatment of HTLA-Chr cells with L-Buthionine-sulfoximine, an inhibitor of GSH biosynthesis, markedly reduces their tumorigenic potential that is instead enhanced by the exposure to N-Acetylcysteine, able to promote GSH synthesis.
Collectively, these results demonstrate that GSH and GSH-related responses play a crucial role in the acquisition of MDR and suggest that GSH level monitoring is an efficient strategy to early identify the onset of drug resistance and to control the patient’s response to therapy.
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