Antitumoral Effect of Phenazine N5,N10-Dioxide Derivatives on Caco-2 Cells

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• 作者：Olga Gisela Pachó ; n ; Amaia Azqueta ; Maria Laura Lavaggi ; Adela Ló ; pez de Cerain ; Edmond Creppy ; Andrew Collins ; Hugo Cerecetto ; Mercedes Gonzá ; lez ; Josep Joan Centelles ; Marta Cascante
• 刊名：Chemical Research in Toxicology
• 出版年：2008
• 出版时间：August 2008
• 年：2008
• 卷：21
• 期：8
• 页码：1578-1585
• 全文大小：285K
• 年卷期：v.21,no.8(August 2008)
• ISSN：1520-5010

文摘

We studied the in vitro antitumoral effect of a series of phenazine di-N-oxide derivatives, named 2-chloroacetylamino-7(8)-nitrophenazine N⁵,N¹⁰-dioxide (1), 2-amino-7(8)-(1,3-dioxol-2-yl)phenazine N⁵,N¹⁰-dioxide (2), 2-chloroacetylamino-7(8)-(1,3-dioxol-2-yl)phenazine N⁵,N¹⁰-dioxide (3), and 2-amino-7(8)-methoxyphenazine N⁵,N¹⁰-dioxide (4), on Caco-2 cells. These phenazine N⁵,N¹⁰-dioxide derivatives belong to our in-house chemical library. The products were selected according to their stereoelectronic characteristics and taking into account their differential cytotoxicity against V79 cells. Human colorectal adenocarcinoma cell line Caco-2 was used to study the cell growth inhibition capacity of these compounds, their capacity of altering the cell cycle and possible induction of apoptosis, DNA fragmentation, and genotoxic damage. The IC₅₀ after 24 h of incubation was lower for 1, 2, and 3 (4.8, 46.8, and 8.2 μM, respectively) than for 4 (474.7 μM). Compound 1 induced arrest in the G2/M phase at 24 and 48 h of treatment and apoptosis at the highest doses at 24 h of treatment. These facts were corroborated with caspase 3, caspase 9, and cytochrome c activation and DNA fragmentation at 24 h of treatment. The derivatives studied induced neither significant single strand breaks nor oxidative damage at the different studied times.We concluded that among the series of N⁵,N¹⁰-dioxide phenazine derivatives analyzed, 1, which contains a nitro moiety and a chloroacetamide group, is the most promising as an antitumoral compound.