title: A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells.
abstract: The NADPH oxidase (Nox) proteins catalyze the regulated formation of reactive oxygen species (ROS), which play key roles as signaling molecules in several physiological and pathophysiological processes. ROS generation by the Nox1 member of the Nox family is necessary for the formation of extracellular matrix (ECM)-degrading, actin-rich cellular structures known as invadopodia. Selective inhibition of Nox isoforms can provide reversible, mechanistic insights into these cellular processes in contrast to scavenging or inhibition of ROS production. Currently no specific Nox inhibitors have been described. Here, by high-throughput screening, we identify a subset of phenothiazines, 2-acetylphenothiazine (here referred to as ML171) (and its related 2-(trifluoromethyl)-phenothiazine) as nanomolar, cell-active, and specific Nox1 inhibitors that potently block Nox1-dependent ROS generation, with only marginal activity on other cellular ROS-producing enzymes and receptors including the other Nox isoforms. ML171 also blocks the ROS-dependent formation of ECM-degrading invadopodia in colon cancer cells. Such effects can be reversed by overexpression of Nox1 protein, which is suggestive of a selective mechanism of inhibition of Nox1 by this compound. These results elucidate the relevance of Nox1-dependent ROS generation in mechanisms of cancer invasion and define ML171 as a useful Nox1 chemical probe and potential therapeutic agent for inhibition of cancer cell invasion.
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Davide
authors: D
authors: Gianni
authors: Nicolas
authors: N
authors: Taulet
authors: Hui
authors: H
authors: Zhang
authors: Celine
authors: C
authors: DerMardirossian
authors: Jeremy
authors: J
authors: Kister
authors: Luis
authors: L
authors: Martinez
authors: William R
authors: WR
authors: Roush
authors: Steven J
authors: SJ
authors: Brown
authors: Gary M
authors: GM
authors: Bokoch
authors: Hugh
authors: H
authors: Rosen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D057166:High-Throughput Screening Assays; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1