title: A novel coumarin-quinone derivative SV37 inhibits CDC25 phosphatases, impairs proliferation, and induces cell death.
abstract: Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach. Here, we describe the synthesis of a new inhibitor (SV37) whose structure is based on both coumarin and quinone moieties. An analytical in vitro approach shows that this compound efficiently inhibits all three purified human CDC25 isoforms (IC50 1-9 µM) in a mixed-type mode. Moreover, SV37 inhibits growth of breast cancer cell lines. In MDA-MB-231 cells, reactive oxygen species generation is followed by pCDK accumulation, a mark of CDC25 dysfunction. Eventually, SV37 treatment leads to activation of apoptosis and DNA cleavage, underlining the potential of this new type of coumarin-quinone structure.
authors.affiliation: Laboratoire "Structure et Réactivité des Systèmes Moléculaires Complexes, UMR CNRS 7565, Université de Lorraine, Campus Bridoux, Rue du Général Delestraint, Metz, France; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, Luxembourg, Luxembourg.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bana
authors.forename: Estelle
authors.initials: E
authors.lastname: Sibille
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Claudia
authors.initials: C
authors.lastname: Cerella
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaimbault
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kirsch
authors.forename: Mario
authors.initials: M
authors.lastname: Dicato
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Denyse
authors.initials: D
authors.lastname: Bagrel
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000737:chemistry*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D053837:DNA Cleavage / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D014764:Viral Proteins; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: C000597311:2-((7-methoxy-2-oxo-2H-chromen-4-yl)methylthio)naphthalene-1,4-dione; D016227:Benzoquinones; D003374:Coumarins; D009285:Naphthoquinones; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; C111491:SV 201 protein, Sendai virus; D014764:Viral Proteins; C004532:quinone; C030123:coumarin; D018844:Cyclin-Dependent Kinases; D020687:cdc25 Phosphatases
keywords: CDC25 inhibitor; apoptosis; breast cancer; coumarin; quinone; reactive oxygen species