2'-Nitroflavone induces cell cycle arrest and apoptosis in HeLa human cervical carcinoma cells.
The mechanism of antitumor action of a synthetic nitroflavone derivative, 2'-nitroflavone, was evaluated in vitro in HeLa human cervix adenocarcinoma cells. We showed that the nitroflavone derivative slowed down the cell cycle at the S phase and increase the population of cells at the G2/M phase after 24h of incubation. The treatment with 2'-nitroflavone also induced an apoptotic response, characterized by an increase of the sub-G1 fraction of cells, by cells with chromatin condensation and membrane blebbing, by a typical ladder of DNA fragmentation and by detection of apoptotic cells stained with Annexin V. The observed apoptosis was regulated by caspase-8 and -9, both contributing to the activation of the effector caspase-3. In addition, inhibitors of caspase-8 or -9 partially protected HeLa cells from 2'-nitroflavone-induced cell death. We also found that 2'-nitroflavone did not affect the total amount of Bax and Bcl-2 proteins, although a translocation of Bax from cytosol to mitochondria was evident after 6h of exposure. Furthermore, 2'-nitroflavone decreased the expression of the anti-apoptotic Bcl-XL protein, induced the release of cytochrome C to cytosol and increased the levels of Fas and Fas-L. Our results indicated that both death receptor and mitochondria-dependent pathways are involved in the apoptotic cell death triggered by 2'-nitroflavone and suggest that this derivative could be a potentially useful agent for the treatment of certain malignancies.
Cárdenas
Mariano G
MG
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 - 1113 Buenos Aires - Argentina.
Blank
Viviana C
VC
Marder
Mariel
M
Roguin
Leonor P
LP
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D047309:Flavones / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D009842:Oligopeptides / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
C532168:2'-nitroflavone; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047309:Flavones; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C096131:valyl-glutamyl-isoleucyl-asparaginyl-cysteinyl-threonyl-arginine; D045304:Cytochromes c; D020169:Caspases