Manipulation of oxidative stress to induce cell death in Ewing's sarcoma family of tumours.
Ewing's sarcoma family of tumours (ESFT) are childhood cancers whose aggressive behaviour and propensity to relapse prompts the need for new treatment approaches. In this study, the role of cellular antioxidants in determining the sensitivity of ESFT cell lines to the cytotoxicity of the antineoplasic agent fenretinide was investigated with a view to identifying targets for the development of new treatment strategies. ESFT cell lines differentially express cellular antioxidants, although cellular glutathione (GSH) was identified as the major determinant of sensitivity to fenretinide. The importance of GSH in ESFT physiology was demonstrated by the depletion of intracellular GSH using l-buthionine (S,R) sulphoximine (BSO), which decreased cell viability. Furthermore, pre-treatment of ESFT cells with BSO sensitised them to fenretinide-induced death. Overall, these results demonstrate that ESFT cells are sensitive to changes in intracellular redox environment, and that targeting specific cellular antioxidants might be a viable strategy in treating ESFT.
Magwere
Tapiwanashe
T
Candlelighter's Children's Cancer Research Group, Cancer Research UK Clinical Centre, St. James's University Hospital, Beckett Street, West Yorkshire, Leeds LS9 7TF, United Kingdom. t.magwere@leeds.ac.uk
Myatt
Stephen S
SS
Burchill
Susan A
SA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism / Q000502:physiology; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D017313:Fenretinide; D019328:Buthionine Sulfoximine; D010088:Oxidoreductases; D005978:Glutathione