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

Authors

  • Mariano G. Cárdenas,

    1. Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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  • Elsa Zotta,

    1. Department of Physiology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
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  • Mariel Marder,

    1. Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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  • Leonor P. Roguin

    Corresponding author
    1. Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
    • IQUIFIB, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina
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    • Fax: +154-11-4962-5457.


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. © 2009 UICC

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