2--nitroflavone and Adenocarcinoma

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.

Topics: Adenocarcinoma; Animals; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspases; Cell Line, Tumor; Cytochromes c; Female; Flavones; Flow Cytometry; In Situ Nick-End Labeling; In Vitro Techniques; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Proto-Oncogene Proteins c-bcl-2; Xenograft Model Antitumor Assays