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Heterogeneous role of the glutathione antioxidant system in modulating the response of ESFT to fenretinide in normoxia and hypoxia.
- Source :
-
PloS one [PLoS One] 2011; Vol. 6 (12), pp. e28558. Date of Electronic Publication: 2011 Dec 08. - Publication Year :
- 2011
-
Abstract
- Glutathione (GSH) is implicated in drug resistance mechanisms of several cancers and is a key regulator of cell death pathways within cells. We studied Ewing's sarcoma family of tumours (ESFT) cell lines and three mechanistically distinct anticancer agents (fenretinide, doxorubicin, and vincristine) to investigate whether the GSH antioxidant system is involved in the reduced sensitivity to these chemotherapeutic agents in hypoxia. Cell viability and death were assessed by the trypan blue exclusion assay and annexin V-PI staining, respectively. Hypoxia significantly decreased the sensitivity of all ESFT cell lines to fenretinide-induced death, whereas the effect of doxorubicin or vincristine was marginal and cell-line-specific. The response of the GSH antioxidant system in ESFT cell lines to hypoxia was variable and also cell-line-specific, although the level of GSH appeared to be most dependent on de novo biosynthesis rather than recycling. RNAi-mediated knockdown of key GSH regulatory enzymes γ-glutamylcysteine synthetase or glutathione disulfide reductase partially reversed the hypoxia-induced resistance to fenretinide, and increasing GSH levels using N-acetylcysteine augmented the hypoxia-induced resistance in a cell line-specific manner. These observations are consistent with the conclusion that the role of the GSH antioxidant system in modulating the sensitivity of ESFT cells to fenretinide is heterogeneous depending on environment and cell type. This is likely to limit the value of targeting GSH as a therapeutic strategy to overcome hypoxia-induced drug resistance in ESFT. Whether targeting the GSH antioxidant system in conjunction with other therapeutics may benefit some patients with ESFT remains to be seen.
- Subjects :
- Acetylcysteine pharmacology
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Cell Count
Cell Hypoxia drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Dietary Supplements
Drug Screening Assays, Antitumor
Fenretinide pharmacology
Gene Knockdown Techniques
Humans
Inhibitory Concentration 50
Intracellular Space drug effects
Intracellular Space metabolism
Models, Biological
RNA, Small Interfering metabolism
Reactive Oxygen Species metabolism
Sarcoma, Ewing enzymology
Antioxidants metabolism
Fenretinide therapeutic use
Glutathione metabolism
Sarcoma, Ewing drug therapy
Sarcoma, Ewing pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 6
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22174837
- Full Text :
- https://doi.org/10.1371/journal.pone.0028558