Roos Cuperus, André B P van Kuilenburg, René Leen, Johannes Bras, Huib N Caron, Godelieve A M Tytgat
Laboratory of Genetic Metabolic Diseases and Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
Free radical biology & medicine 2011 Sep 15To 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. Copyright © 2011 Elsevier Inc. All rights reserved.
Roos Cuperus, André B P van Kuilenburg, René Leen, Johannes Bras, Huib N Caron, Godelieve A M Tytgat. Promising effects of the 4HPR-BSO combination in neuroblastoma monolayers and spheroids. Free radical biology & medicine. 2011 Sep 15;51(6):1213-20
PMID: 21741474
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