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In vitro induction of apoptosis and in vivo effects of a flavone nitroderivative in murine mammary adenocarcinoma cells.

Abstract
We explored the in vitro and in vivo mechanism of antitumor action of the synthetic flavonoid 2'-nitroflavone on LM3 murine mammary adenocarcinoma cells. In vitro assays showed that 2'-nitroflavone increased the population of LM3 hypodiploid cells and produced a typical ladder of DNA fragmentation. Apoptotic cell death was also characterized by the activation of caspase-8, -9 and -3, by an increment in the expression levels of the proapoptotic protein Bax and by the release of cytochrome c to cytosol. The in vivo effect of 2'-nitroflavone on tumor growth was studied in BALB/c mice injected subcutaneously with LM3 cells. Results showed that tumor volume and weight were significantly reduced at doses of 10 and 40 mg/kg of 2'-nitroflavone, respectively. Apoptotic cells were identified by TUNEL assay in tumor slices from mice treated with 10 mg/kg of 2'-nitroflavone. Western blot analysis of tumor lysate supernatants from treated mice revealed an upregulation of the total levels of Bax and Fas receptor. In addition, administration of 40 mg/kg of 2'-nitroflavone to nontumor-bearing mice showed no histopathological effects on different organ tissues. This is the first report of the in vivo growth inhibitory effect of 2'-nitroflavone as an apoptotic agent likely useful for mammary adenocarcinoma treatment.
AuthorsMariano G Cárdenas, Elsa Zotta, Mariel Marder, Leonor P Roguin
JournalInternational journal of cancer (Int J Cancer) Vol. 125 Issue 1 Pg. 222-8 (Jul 01 2009) ISSN: 1097-0215 [Electronic] United States
PMID19358271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2'-nitroflavone
  • Flavones
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Cytochromes c
  • Caspases
Topics
  • Adenocarcinoma (drug therapy, metabolism, pathology)
  • Animals
  • Apoptosis (drug effects)
  • Blotting, Western
  • Caspases (metabolism)
  • Cell Line, Tumor
  • Cytochromes c (metabolism)
  • Female
  • Flavones (therapeutic use)
  • Flow Cytometry
  • In Situ Nick-End Labeling
  • In Vitro Techniques
  • Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein (metabolism)

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