Glutathione-mediated antioxidant response and aerobic metabolism

two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma

Renata Colla, Alberto Izzotti, Chiara De Ciucis, Daniela Fenoglio, Silvia Ravera, Andrea Speciale, Roberta Ricciarelli, Annalisa Furfaro, Alessandra Pulliero, Mario Passalacqua, Nicola Traverso, Maria Adelaide Pronzato, Cinzia Domenicotti, Barbara Marengo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)70715-70737
Number of pages23
JournalOncotarget
Volume7
Issue number43
DOIs
Publication statusPublished - Oct 25 2016

Fingerprint

Multiple Drug Resistance
Etoposide
Neuroblastoma
Glutathione
Antioxidants
Buthionine Sulfoximine
Acetylcysteine
Drug Resistance
Sulfhydryl Compounds
Catalase
Doxorubicin
Cell Death
Up-Regulation
Pediatrics
Cell Line
Membranes
Therapeutics
Pharmaceutical Preparations
Neoplasms

Keywords

  • Journal Article

Cite this

Glutathione-mediated antioxidant response and aerobic metabolism : two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma. / Colla, Renata; Izzotti, Alberto; De Ciucis, Chiara; Fenoglio, Daniela; Ravera, Silvia; Speciale, Andrea; Ricciarelli, Roberta; Furfaro, Annalisa; Pulliero, Alessandra; Passalacqua, Mario; Traverso, Nicola; Pronzato, Maria Adelaide; Domenicotti, Cinzia; Marengo, Barbara.

In: Oncotarget, Vol. 7, No. 43, 25.10.2016, p. 70715-70737.

Research output: Contribution to journalArticle

Colla, R, Izzotti, A, De Ciucis, C, Fenoglio, D, Ravera, S, Speciale, A, Ricciarelli, R, Furfaro, A, Pulliero, A, Passalacqua, M, Traverso, N, Pronzato, MA, Domenicotti, C & Marengo, B 2016, 'Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma', Oncotarget, vol. 7, no. 43, pp. 70715-70737. https://doi.org/10.18632/oncotarget.12209
Colla, Renata ; Izzotti, Alberto ; De Ciucis, Chiara ; Fenoglio, Daniela ; Ravera, Silvia ; Speciale, Andrea ; Ricciarelli, Roberta ; Furfaro, Annalisa ; Pulliero, Alessandra ; Passalacqua, Mario ; Traverso, Nicola ; Pronzato, Maria Adelaide ; Domenicotti, Cinzia ; Marengo, Barbara. / Glutathione-mediated antioxidant response and aerobic metabolism : two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma. In: Oncotarget. 2016 ; Vol. 7, No. 43. pp. 70715-70737.
@article{a8b8752ae798490dbe60cf58d15ec379,
title = "Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma",
abstract = "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.",
keywords = "Journal Article",
author = "Renata Colla and Alberto Izzotti and {De Ciucis}, Chiara and Daniela Fenoglio and Silvia Ravera and Andrea Speciale and Roberta Ricciarelli and Annalisa Furfaro and Alessandra Pulliero and Mario Passalacqua and Nicola Traverso and Pronzato, {Maria Adelaide} and Cinzia Domenicotti and Barbara Marengo",
year = "2016",
month = "10",
day = "25",
doi = "10.18632/oncotarget.12209",
language = "English",
volume = "7",
pages = "70715--70737",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "43",

}

TY - JOUR

T1 - Glutathione-mediated antioxidant response and aerobic metabolism

T2 - two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma

AU - Colla, Renata

AU - Izzotti, Alberto

AU - De Ciucis, Chiara

AU - Fenoglio, Daniela

AU - Ravera, Silvia

AU - Speciale, Andrea

AU - Ricciarelli, Roberta

AU - Furfaro, Annalisa

AU - Pulliero, Alessandra

AU - Passalacqua, Mario

AU - Traverso, Nicola

AU - Pronzato, Maria Adelaide

AU - Domenicotti, Cinzia

AU - Marengo, Barbara

PY - 2016/10/25

Y1 - 2016/10/25

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.18632/oncotarget.12209

DO - 10.18632/oncotarget.12209

M3 - Article

VL - 7

SP - 70715

EP - 70737

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 43

ER -