title: Peptide screen identifies a new NADPH oxidase inhibitor: impact on cell migration and invasion.
abstract: The NADPH oxidase proteins catalyse the formation of superoxide anion which act as signalling molecules in physiological and pathological processes. Nox1-dependent NADPH oxidase is expressed in heart, lung, colon, blood vessels and brain. Different strategies involving Nox1 inhibition based on diphenylene iodonium derivatives are currently tested for colorectal cancer therapy. Here, after peptides screening on Nox1-dependent NADPH oxidase assay in HT-29 cells, we identify a peptide (referred to as NF02), cell-active, that potently block Nox1-dependent reactive oxygen species generation. Study of DEPMPO adduct formation by electron paramagnetic resonance showed that NF02 has no superoxide scavenging activity and no impact on cellular reactive oxygen species-producing enzymes such xanthine oxidase. NF02 was not cytotoxic, inhibited reactive oxygen species production of reconstituted Nox1/Noxo1/Noxa1 complex in HEK293 and did not decrease Nox2 dependent cellular NADPH oxidase reactive oxygen species production. Finally, NF02 inhibited cell migration and invasion of colorectal cancer cells which is consistent with the described impact of Nox1 inhibitors on cell migration. NF02 peptide is a new NADPH oxidase inhibitor specific for Nox1 over Nox2 and xanthine oxidase which might represent a useful Nox1 tool with potential therapeutic insights.
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mousslim
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pagano
authors.affiliation: Aix-Marseille Univ, INSERM UMR 639, Parc Scientifique de Luminy, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andreotti
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Garrouste
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thuault
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Parat
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France.
authors.forename: José
authors.initials: J
authors.lastname: Luis
authors.affiliation: Aix-Marseille Univ, CNRS, UMR 7273, ICR SMBSO, Marseille, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Culcasi
authors.affiliation: Aix-Marseille Univ, CNRS, UMR 7273, ICR SMBSO, Marseille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thétiot-Laurent
authors.affiliation: Aix-Marseille Univ, CNRS, UMR 7273, ICR SMBSO, Marseille, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Pietri
authors.affiliation: Aix-Marseille Univ, INSERM UMR 639, Parc Scientifique de Luminy, Marseille, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
authors.affiliation: Aix Marseille Univ, INSERM, CRO2, Faculté de Pharmacie, Marseille, France. Electronic address: herve.kovacic@univ-amu.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Kovacic
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human
keywords: Cell migration; EPR spin trapping; NADPH oxidase; Nox1; Reactive oxygen species; Superoxide