title: Novel Phenazine 5,10-Dioxides Release OH in Simulated Hypoxia and Induce Reduction of Tumour Volume In Vivo.
abstract: Phenazine 5,10-dioxides (PDOs) are a new class of bioreductive cytotoxins, which could act towards tumours containing hypoxic regions. The PDOs selective-hypoxic bioreduction was probed in vitro; however, the mechanism of action has not been completely explained. Besides, PDOs in vivo antitumour activities have not been demonstrated hitherto. We study the mechanism of hypoxic/normoxic cytotoxicity of PDO representative members. Electron spin resonance is used to confirm (•)OH production, alkaline comet assay to determine genotoxicity, and gel electrophoresis and flow cytometry to analyze DNA fragmentation and cell cycle distribution. Chemically induced rat breast tumours are employed to evaluate in vivo activities. For the most selective cytotoxin, 7(8)-bromo-2-hydroxyphenazine 5,10-dioxide (PDO1), exclusive hypoxic (•)OH production is evidenced, while for the unselective ones, (•)OH is produced in both conditions (normoxia and simulated hypoxia). In normoxia (Caco-2 cells), PDO1 induces cell-cycle arrest and DNA fragmentation but does not significantly induce apoptosis neither at IC(50) nor IC(80). No difference in the comet-assay scores are observed in normoxia and simulated hypoxia being the unselective 2-amino-7(8)-bromophenazine 5,10-dioxide (PDO2) the most genotoxic. The in vivo efficacy with the absence of systemic toxicity of PDO1 and PDO2 is checked out. Results from this study highlight the potential of PDOs as new therapeutics for cancer.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: María L
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cabrera
authors.forename: Cristina
authors.initials: C
authors.lastname: Pintos
authors.forename: Carolina
authors.initials: C
authors.lastname: Arredondo
authors.forename: Gisela
authors.initials: G
authors.lastname: Pachón
authors.forename: Jorge
authors.initials: J
authors.lastname: Rodríguez
authors.forename: Stella
authors.initials: S
authors.lastname: Raymondo
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Pacheco
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Claudio
authors.initials: C
authors.lastname: Olea-Azar
authors.forename: Adela
authors.initials: A
authors.lastname: López de Ceráin
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
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