Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma.
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.
Department of Experimental Medicine, University of Genova, Genova, Italy.
Renata
R
Colla
Department of Health Sciences, University of Genova, Genova, Italy.|IRCCS AOU San Martino IST Genova, Genova, Italy.
Alberto
A
Izzotti
Department of Experimental Medicine, University of Genova, Genova, Italy.
Chiara
C
De Ciucis
Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genova, Genova, Italy.
Daniela
D
Fenoglio
Department of Pharmacy, University of Genova, Genova, Italy.
Silvia
S
Ravera
Department of Experimental Medicine, University of Genova, Genova, Italy.
Andrea
A
Speciale
Department of Experimental Medicine, University of Genova, Genova, Italy.
Roberta
R
Ricciarelli
Giannina Gaslini Institute, Genova, Italy.
Anna Lisa
AL
Furfaro
Department of Health Sciences, University of Genova, Genova, Italy.
Alessandra
A
Pulliero
Department of Experimental Medicine, University of Genova, Genova, Italy.
Mario
M
Passalacqua
Department of Experimental Medicine, University of Genova, Genova, Italy.
Nicola
N
Traverso
Department of Experimental Medicine, University of Genova, Genova, Italy.
Maria Adelaide
MA
Pronzato
Department of Experimental Medicine, University of Genova, Genova, Italy.
Cinzia
C
Domenicotti
Department of Experimental Medicine, University of Genova, Genova, Italy.
Barbara
B
Marengo
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation
D000975:Antioxidants; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D019328:Buthionine Sulfoximine; D005047:Etoposide; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D000111:Acetylcysteine
aerobic metabolism; antioxidants; glutathione; multi-drug resistance; neuroblastoma
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