title: Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells.
abstract: Quinone-containing molecules have been developed against cancer mainly for their redox cycling ability leading to reactive oxygen species (ROS) formation. We have previously shown that donor-acceptor phenylaminonaphthoquinones are biologically active against a panel of cancer cells. In this report, we explored the mechanisms involved in cancer cell growth inhibition caused by two phenylaminonaphthoquinones, namely Q7 and Q9, with or without ascorbate (ASC). The results show that Q7 and Q9 are both redox cyclers able to form ROS, which strongly inhibit the proliferation of T24 cells. Q9 was a better redox cycler than Q7 because of marked stabilization of the semiquinone radical species arising from its reduction by ascorbate. Indeed, ASC dramatically enhances the inhibitory effect of Q9 on cell proliferation. Q9 plus ASC impairs the cell cycle, causing a decrease in the number of cells in the G2/M phase without involving other cell cycle regulating key proteins. Moreover, Q9 plus ASC influences the MAPK signaling pathways, provoking the appearance of a senescent cancer cell phenotype and ultimately leading to necrotic-like cell death. Because cellular senescence limits the replicative capacity of cells, our results suggest that induction of senescence may be exploited as a basis for new approaches to cancer therapy.
authors.affiliation: Laboratorio de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: K B
authors.initials: KB
authors.lastname: Felipe
authors.forename: J
authors.initials: J
authors.lastname: Benites
authors.forename: C
authors.initials: C
authors.lastname: Glorieux
authors.forename: B
authors.initials: B
authors.lastname: Sid
authors.forename: M
authors.initials: M
authors.lastname: Valenzuela
authors.forename: M R
authors.initials: MR
authors.lastname: Kviecinski
authors.forename: R C
authors.initials: RC
authors.lastname: Pedrosa
authors.forename: J A
authors.initials: JA
authors.lastname: Valderrama
authors.forename: Ph
authors.initials: P
authors.lastname: Levêque
authors.forename: B
authors.initials: B
authors.lastname: Gallez
authors.forename: J
authors.initials: J
authors.lastname: Verrax
authors.forename: P
authors.initials: P
authors.lastname: Buc Calderon
mesh_terms: D000627:Aminophenols / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D053148:Caspase 3 / Q000032:analysis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000494:pharmacology*; D009336:Necrosis; D010084:Oxidation-Reduction; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: C581644:2-(4-hydroxyanilino)-1,4-naphthoquinone; C581645:2-(4-methoxyanilino)-1,4-naphthoquinone; D000627:Aminophenols; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D007093:Imidazoles; D009285:Naphthoquinones; D011725:Pyridines; D017382:Reactive Oxygen Species; C505407:CASP3 protein, human; D053148:Caspase 3; D001205:Ascorbic Acid; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole