title: A small molecule that induces reactive oxygen species via cellular glutathione depletion.
abstract: 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(c)⁻, 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 glutathione metabolism, in cancer treatment.
authors.affiliation: *Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kawamura
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.affiliation: *Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017920:Antiporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D005978:Glutathione / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D017382:Reactive Oxygen Species / Q000378:metabolism*; D020298:U937 Cells; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017920:Antiporters; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D005978:Glutathione