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 Radic Biol Med. 2011 Sep 15;51(6):1213-20. doi: 10.1016/j.freeradbiomed.2011.06.019. Epub 2011 Jun 23.
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.
为了增强芬维 A 酯（4HPR）诱导的神经母细胞瘤活性氧（ROS）的疗效，我们在神经母细胞瘤细胞系和球体中，将 4HPR 与谷胱甘肽（GSH）合成抑制剂丁硫氨酸亚砜胺（BSO）联合使用，后者是一种三维肿瘤模型。4HPR 暴露（2.5-10 μM，24 小时）导致 ROS 诱导（114-633%）和 GSH 水平增加（68-120%）。在存在 BSO（25-100 μM，24 小时）的情况下，观察到 GSH 耗竭达到基础水平的 80%。与单独使用 4HPR 相比，4HPR-BSO 联合使用导致 ROS 水平略有增加（1.1-1.3 倍），同时细胞毒性增加（110-150%）。与 4HPR 相比，我们观察到每个细胞系的 ROS 诱导能力与 4HPR-BSO 诱导的细胞毒性增加之间存在相关性。未观察到基线抗氧化剂水平与对 4HPR 或 BSO 的敏感性之间存在显著相关性。在球体中，4HPR-BSO 诱导强烈的协同生长抑制和凋亡诱导。我们的数据表明，BSO 增强了 4HPR 在 ROS 产生细胞系中的神经母细胞瘤单层和球体中的细胞毒性作用。这表明 4HPR-BSO 联合可能是治疗神经母细胞瘤的一种有前途的新策略。
