Antitumoral effect of phenazine N5,N10-dioxide derivatives on Caco-2 cells.
We studied the in vitro antitumoral effect of a series of phenazine di- N-oxide derivatives, named 2-chloroacetylamino-7(8)-nitrophenazine N(5), N(10)-dioxide (1), 2-amino-7(8)-(1,3-dioxol-2-yl)phenazine N(5), N(10)-dioxide (2), 2-chloroacetylamino-7(8)-(1,3-dioxol-2-yl)phenazine N(5), N(10)-dioxide (3), and 2-amino-7(8)-methoxyphenazine N(5), N(10)-dioxide (4), on Caco-2 cells. These phenazine N(5), N(10)-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 IC 50 after 24 h of incubation was lower for 1, 2, and 3 (4.8, 46.8, and 8.2 microM, respectively) than for 4 (474.7 microM). 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 N(5), N(10)-dioxide phenazine derivatives analyzed, 1, which contains a nitro moiety and a chloroacetamide group, is the most promising as an antitumoral compound.
Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Av. Diagonal 645, 08028 Barcelona, Spain.
Olga Gisela
OG
Pachón
Amaia
A
Azqueta
Maria Laura
ML
Lavaggi
Adela
A
López de Cerain
Edmond
E
Creppy
Andrew
A
Collins
Hugo
H
Cerecetto
Mercedes
M
González
Josep Joan
JJ
Centelles
Marta
M
Cascante
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D020552:Comet Assay; D045304:Cytochromes c / Q000096:biosynthesis; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D005562:Formazans / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010619:Phenazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000378:metabolism
D000970:Antineoplastic Agents; D005562:Formazans; D010619:Phenazines; D013778:Tetrazolium Salts; C079782:MTT formazan; C071996:phenazine di-N-oxide; D045304:Cytochromes c; D020169:Caspases