2011
DOI: 10.1371/journal.pone.0028558
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Heterogeneous Role of the Glutathione Antioxidant System in Modulating the Response of ESFT to Fenretinide in Normoxia and Hypoxia

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 an… Show more

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Cited by 6 publications
(4 citation statements)
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“…It is thus possible that while in normoxia the metformin- induced glycolytic shift is able to generate a stress sufficient for cells to induce direct activation of AMPK, in hypoxia the accumulation of HIF1 may make respiration more efficient [65] and protect cells from damages, including energy perturbations induced by metformin. Besides confirming previous evidence which showed how hypoxia may be amajor factor in the tumor microenvironment of Ewing sarcoma [41] , [43] , [63] , our findings suggest a note of caution in the general enthusiasm that is linked to clinical use metformin and other biguanides. Although the effects of metformin in tumor prevention seem to be really encouraging, its efficacy in tumor therapy is still under evaluation.…”
Section: Discussionsupporting
confidence: 89%
See 1 more Smart Citation
“…It is thus possible that while in normoxia the metformin- induced glycolytic shift is able to generate a stress sufficient for cells to induce direct activation of AMPK, in hypoxia the accumulation of HIF1 may make respiration more efficient [65] and protect cells from damages, including energy perturbations induced by metformin. Besides confirming previous evidence which showed how hypoxia may be amajor factor in the tumor microenvironment of Ewing sarcoma [41] , [43] , [63] , our findings suggest a note of caution in the general enthusiasm that is linked to clinical use metformin and other biguanides. Although the effects of metformin in tumor prevention seem to be really encouraging, its efficacy in tumor therapy is still under evaluation.…”
Section: Discussionsupporting
confidence: 89%
“…Interestingly, the majority of EWS-FLI1 regulated genes showed opposite transcriptional effects in normoxia or hypoxia conditions, such as the survival factor, IGFBP-3, which has previously been shown to be suppressed by EWS-FLI1 in normoxia but highly upregulated under hypoxia or by the pro-apoptotic gene BAX, strongly downregulated in hypoxia [41]. As recently reported, these changes may contribute to HIF-1α dependent protection of Ewing cells from anti-cancer drug- or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis [43], [63]. In addition, hypoxia has a major effect on cell metabolism.…”
Section: Discussionmentioning
confidence: 87%
“…In vitro , hypoxia up-regulates EWS-FLI1 protein and modifies its transcriptional profile, promoting genes involved in tumor progression [6]. Hypoxic ES cells exhibit an enhanced anchorage-independent growth, invasiveness, and resistance to apoptosis induced by exogenous factors [6-9, 38]. However, the mechanisms of these effects remain unclear.…”
Section: Discussionmentioning
confidence: 99%
“…These cancer stem cells are believed to be responsible for tumor initiation, as well as subsequent relapse and metastases. Since hypoxia has been shown to promote an aggressive phenotype of various tumors, including Ewing sarcoma, these data indicate that the proliferative effect of NPY in hypoxic cancer stem cells may lead to their propagation and facilitate further tumor progression (Aryee et al, 2010; Batra et al, 2004; Dunst et al, 2001; Kilic et al, 2007; Knowles et al, 2010; Magwere and Burchill, 2011; Tilan et al, 2013b). This hypothesis is currently under investigation in our laboratory.…”
Section: Npy In Regulation Of Tumor Cell Proliferationmentioning
confidence: 96%