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2'-Nitroflavone induces cell cycle arrest and apoptosis in HeLa human cervical carcinoma cells.

Abstract
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.
AuthorsMariano G Cárdenas, Viviana C Blank, Mariel Marder, Leonor P Roguin
JournalCancer letters (Cancer Lett) Vol. 268 Issue 1 Pg. 146-57 (Sep 08 2008) ISSN: 0304-3835 [Print] Ireland
PMID18485587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2'-nitroflavone
  • FASLG protein, human
  • Fas Ligand Protein
  • Flavones
  • Oligopeptides
  • Proto-Oncogene Proteins c-bcl-2
  • valyl-glutamyl-isoleucyl-asparaginyl-cysteinyl-threonyl-arginine
  • Cytochromes c
  • Caspases
Topics
  • Apoptosis (drug effects)
  • Caspases (metabolism)
  • Cell Cycle (drug effects)
  • Cytochromes c (metabolism)
  • Fas Ligand Protein (metabolism)
  • Female
  • Flavones (metabolism, pharmacology)
  • HeLa Cells
  • Humans
  • Oligopeptides (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Uterine Cervical Neoplasms (pathology)

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