Chemically synthesized
Biological activity
glutathione depletion
Induction of excessive levels of reactive oxygen species (ROS) by small molecule compounds has been considered as 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 recently identified NPD926, a small molecule that induces rapid cell death in cancer cells. By a combination of two comprehensive and complementary approaches, proteomic profiling and affinity purification, combined with the subsequent biochemical assays, we elucidated the mechanism of action underlying NPD926-induced cell death: conjugation with glutathione mediated by glutathione S-transferases, 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 xc, a cystine-glutamate antiporter considered as a potential therapeutic target in cancers including cancer stem cells. These data show the effectiveness of a newly identified ROS inducer, which targets glutathione metabolism, in cancer treatment.
  • Kawamura T, Kondoh Y, Muroi M, Kawatani M, Osada H.: A small molecule that induces reactive oxygen species via cellular glutathione depletion.
    Biochem J, 463(1): 53-63 (2014) PMID: 25011393 [ doi: 10.1042/BJ20140669 ]
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