The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38MAPK activity

Myatt, Stephen S.; Burchill, Susan A.

doi:10.1038/sj.onc.1210705

Cited by 26 publications

(25 citation statements)

References 40 publications

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“…The EWS/Fli1 transcription factor plays a major role in regulating apoptosis in ESFT both in vitro and in vivo [35], [36] and enhances the drug resistant phenotype of ESFT cells in hypoxia in a HIF-1α-dependent manner [37]. Hence to eliminate the influence of different EWS/Fli1 fusion types on sensitivity to fenretinide toxicity in this study we used RDES and SKES-1 cell lines that are both EWS/Fli1 fusion type II and hemizygous null for p53 to study the role of GSH in greater detail.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Role of the Glutathione Antioxidant System in Modulating the Response of ESFT to Fenretinide in Normoxia and Hypoxia

Magwere

Burchill

2011

PLoS ONE

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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.

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Section: Discussionmentioning

confidence: 99%

Heterogeneous Role of the Glutathione Antioxidant System in Modulating the Response of ESFT to Fenretinide in Normoxia and Hypoxia

Magwere

Burchill

2011

PLoS ONE

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“…New therapeutic approaches based on Ewing sarcoma biology, such as antivascular endothelial growth factors,45 46 anti-insulin-like growth factors,47 48 retinoic acid derivatives49 50 and agents that interfere with the mammalian target of rapamycin51 are being investigated and represent promising future therapeutic options.…”

Section: Discussionmentioning

confidence: 99%

Peripheral primitive neuroectodermal tumour of the orbit

Romero

Castano²,

Abelairas

et al. 2010

British Journal of Ophthalmology

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Peripheral primitive neuroectodermal tumours (pPNETs) are a group of soft-tissue tumours of neuroepithelial origin that arise outside the central and sympathetic nervous system. Orbital location is infrequent, and to the best of the authors' knowledge only 16 cases have been reported in the literature. With this article, the authors report the demographics and clinical characteristics, diagnostic features, differential diagnosis, prognosis and therapeutic options of primary orbital peripheral primitive neuroectodermal tumour, based on their patients and on the cases reported in the literature to date. A differential diagnosis should be made with other small round cell tumours; immunohistochemical and ultrastructural techniques are essential for this purpose. Although bone invasion and extraorbital extension are possible, systemic metastases are uncommon in the cases of orbital pPNETs. Surgery has been the initial treatment in most cases; chemotherapy with or without radiotherapy is considered the best additional treatment. The orbital pPNET could be less aggressive than other forms of pPNETs, since most of the patients reported were alive after the follow-up period (at least 6 months).

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“…TC-32 cells were electroporated with MRP-1 siRNA (400 n; siGenome SMARTpool M-007308-01-0005, Dharmacon, Lafayette, CO, USA) or scrambled siRNA control (400 n; Silencer Negative control, Ambion, Austin, TX, USA) (Myatt and Burchill, 2008). MRP-1 protein expression, detected by western blot, was normalised to the loading control and relative to the scrambled siRNA control.…”

Section: Methodsmentioning

confidence: 99%

Detection and characterisation of multi-drug resistance protein 1 (MRP-1) in human mitochondria

Roundhill

Burchill

2012

Br J Cancer

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Background:Overexpression of plasma membrane multi-drug resistance protein 1 (MRP-1) can lead to multidrug resistance. In this study, we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues.Methods:MRP-1 expression and subcellular localisation in normal and cancer cells and tissues was examined by differential centrifugation and western blotting, and immunofluorescence microscopy. Viable mitochondria were isolated and MRP-1 efflux activity measured using the calcein-AM functional assay. MRP-1 expression was increased using retroviral infection and specific overexpression confirmed by RNA array. Cell viability was determined by trypan blue exclusion and annexin V-propidium iodide labelling of cells.Results:MRP-1 was detected in the mitochondria of cancer and normal cells and tissues. The efflux activity of mitochondrial MRP-1 was more efficient (55–64%) than that of plasma membrane MRP-1 (11–22% P<0.001). Induced MRP-1 expression resulted in a preferential increase in mitochondrial MRP-1, suggesting selective targeting to this organelle. Treatment with a non-lethal concentration of doxorubicin (0.85 n, 8 h) increased mitochondrial and plasma membrane MRP-1, increasing resistance to MRP-1 substrates. For the first time, we have identified MRP-1 with efflux activity in human mitochondria.Conclusion:Mitochondrial MRP-1 may be an exciting new therapeutic target where historically MRP-1 inhibitor strategies have limited clinical success.

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The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38MAPK activity

Cited by 26 publications

References 40 publications

Heterogeneous Role of the Glutathione Antioxidant System in Modulating the Response of ESFT to Fenretinide in Normoxia and Hypoxia

Heterogeneous Role of the Glutathione Antioxidant System in Modulating the Response of ESFT to Fenretinide in Normoxia and Hypoxia

Peripheral primitive neuroectodermal tumour of the orbit

Detection and characterisation of multi-drug resistance protein 1 (MRP-1) in human mitochondria

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