title: Promising effects of the 4HPR-BSO combination in neuroblastoma monolayers and spheroids.
abstract: To enhance the efficacy of fenretinide (4HPR)-induced reactive oxygen species (ROS) in neuroblastoma, 4HPR was combined with buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, in neuroblastoma cell lines and spheroids, the latter being a three-dimensional tumor model. 4HPR exposure (2.5-10 μM, 24 h) resulted in ROS induction (114-633%) and increased GSH levels (68-120%). A GSH depletion of 80% of basal levels was observed in the presence of BSO (25-100 μM, 24 h). The 4HPR-BSO combination resulted in slightly increased ROS levels (1.1- to 1.3-fold) accompanied by an increase in cytotoxicity (110-150%) compared to 4HPR treatment alone. A correlation was observed between the ROS-inducing capacity of each cell line and the increase in cytotoxicity induced by 4HPR-BSO compared to 4HPR. No significant correlation between baseline antioxidant levels and sensitivity to 4HPR or BSO was observed. In spheroids, 4HPR-BSO induced a strong synergistic growth retardation and induction of apoptosis. Our data show that BSO increased the cytotoxic effects of 4HPR in neuroblastoma monolayers and spheroids in ROS-producing cell lines. This indicates that the 4HPR-BSO combination might be a promising new strategy in the treatment of neuroblastoma.
authors: Laboratory of Genetic Metabolic Diseases and Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
authors: Roos
authors: R
authors: Cuperus
authors: André B P
authors: AB
authors: van Kuilenburg
authors: René
authors: R
authors: Leen
authors: Johannes
authors: J
authors: Bras
authors: Huib N
authors: HN
authors: Caron
authors: Godelieve A M
authors: GA
authors: Tytgat
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D017313:Fenretinide / Q000494:pharmacology*; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018874:Spheroids, Cellular
chemical_list: D006131:Growth Inhibitors; D017382:Reactive Oxygen Species; D017313:Fenretinide; D019328:Buthionine Sulfoximine; D005978:Glutathione