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 language | English |
|---|---|
| Pages (from-to) | 70715-70737 |
| Number of pages | 23 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 43 |
| DOIs | |
| Publication status | Published - Oct 25 2016 |
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Keywords
- Journal Article
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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 journal › Article
}
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
C2 - 27683112
VL - 7
SP - 70715
EP - 70737
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 43
ER -