A small molecule that induces reactive oxygen species via cellular glutathione depletion
A small molecule that induces reactive oxygen species via cellular glutathione depletion
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DOI：
10.1042/bj20140669
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发表时间：
2014-10-01
影响因子：
4.1
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kawamura, Tatsuro;Kondoh, Yasumitsu;Osada, Hiroyuki
小分子化合物诱导过高水平的ROS被认为是一种潜在的有效治疗肿瘤细胞的策略，而癌细胞往往受到慢性氧化应激的影响。然而，阐明生物活性化合物的作用机制通常是一个耗时的过程。我们最近发现了NPD926，这是一种能诱导癌细胞快速死亡的小分子。结合蛋白质组学和亲和纯化两种综合和互补的方法，结合后续的生化分析，我们阐明了NPD926诱导细胞死亡的作用机制：由GST介导的与谷胱甘肽的结合，细胞谷胱甘肽的耗竭和随后的ROS产生。与未转化的成纤维细胞相比，NPD926在KRAS转化的成纤维细胞中具有优先诱导效应。此外，NPD926使细胞对系统x的抑制剂敏感，系统x是一种半胱氨酸-谷氨酸逆向转运体，被认为是包括癌症干细胞在内的癌症的潜在治疗靶点。这些数据显示了一种新发现的针对谷胱甘肽代谢的ROS诱导剂在癌症治疗中的有效性。
Induction of excessive levels of reactive oxygen species (ROS) by small-molecule compounds has been considered a potentially effective therapeutic strategy against cancer cells, which are often subjected to chronic oxidative stress. However, to elucidate the mechanisms of action of bioactive compounds is generally a time-consuming process. We have recently identified NPD926, a small molecule that induces rapid cell death in cancer cells. Using a combination of two comprehensive and complementary approaches, proteomic profiling and affinity purification, together with the subsequent biochemical assays, we have elucidated the mechanism of action underlying NPD926-induced cell death: conjugation with glutathione mediated by GST, depletion of cellular glutathione and subsequent ROS generation. NPD926 preferentially induced effects in KRAS-transformed fibroblast cells, compared with their untransformed counterparts. Furthermore, NPD926 sensitized cells to inhibitors of system x, a cystine-glutamate antiporter considered to be a potential therapeutic target in cancers including cancer stem cells. These data show the effectiveness of a newly identified ROS inducer, which targets glntathione metabolism, in cancer treatment.