title: Growth inhibitory effects of 3'-nitro-3-phenylamino nor-beta-lapachone against HL-60: a redox-dependent mechanism.
abstract: In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.
authors.affiliation: Depto. de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE 60430-270, Brazil.
authors.forename: A J
authors.initials: AJ
authors.lastname: Araújo
authors.forename: A A
authors.initials: AA
authors.lastname: de Souza
authors.forename: E N
authors.initials: EN
authors.lastname: da Silva Júnior
authors.forename: J D B
authors.initials: JD
authors.lastname: Marinho-Filho
authors.forename: M A B F
authors.initials: MA
authors.lastname: de Moura
authors.forename: D D
authors.initials: DD
authors.lastname: Rocha
authors.forename: M C
authors.initials: MC
authors.lastname: Vasconcellos
authors.forename: C O
authors.initials: CO
authors.lastname: Costa
authors.forename: C
authors.initials: C
authors.lastname: Pessoa
authors.forename: M O
authors.initials: MO
authors.lastname: de Moraes
authors.forename: V F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: F C
authors.initials: FC
authors.lastname: de Abreu
authors.forename: A V
authors.initials: AV
authors.lastname: Pinto
authors.forename: R C
authors.initials: RC
authors.lastname: Montenegro
authors.forename: L V
authors.initials: LV
authors.lastname: Costa-Lotufo
authors.forename: M O F
authors.initials: MO
authors.lastname: Goulart
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D018922:HL-60 Cells; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C574725:2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho(1,2-b)furan-4,5-dione; D000970:Antineoplastic Agents; D001572:Benzofurans; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C574726:nor-beta-lapachone