Growth inhibitory effects of 3鈥?nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

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• 作者：A.J. Araú ; jo^a ; A.A. de Souza^b ; E.N. da Silva Jú ; nior^c ; ^d ; J.D.B. Marinho-Filho^a ; M.A.B.F. de Moura^b ; D.D. Rocha^a ; M.C. Vasconcellos^e ; C.O. Costa^b ; C. Pessoa^a ; M.O. de Moraes^a ; V.F. Ferreira^f ; F.C. de Abreu^b ; A.V. Pinto^d ; R.C. Montenegro^g ; L.V. Costa-Lotufo^a ; ^{costalotufo@gmail.com} ; M.O.F. Goulart^b ; ^h ; ^{mofg@qui.ufal.br}
• 关键词：Apoptosis ; Cytotoxicity ; DNA sensors ; Nitroquinone ; Nor-beta-lapachone ; Bioelectrochemistry
• 刊名：Toxicology in Vitro
• 出版年：2012
• 期刊代码：48_08872333
• 类别：pha
• 出版时间：June, 2012
• 卷：26
• 期：4
• 页码：585-594
• 文件大小：1006 K

摘要

In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3鈥?nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO₂) 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/TBABF₄) 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 QPhNO₂. QPhNO₂ 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 QPhNO₂ 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.