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Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells
N J Panaro1, N C Popescu, S R Harris
1Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Abstract:
Flavone acetic acid (FAA) is a synthetic flavonoid that demonstrated extraordinary anti-tumour properties in murine models but was not effective in clinical trials. In an effort to better understand the molecular mechanisms by which FAA asserts its tumouricidal activities, we have examined the effect of FAA on the cell cycle. We observed FAA-mediated G2/M cell cycle arrest in mammary carcinoma cells at a concentration previously demonstrated to have anti-tumour effects in rodent models. The cell cycle arrest was accompanied by an increase in the P34cdc2 (cdc2) cyclin-dependent kinase activity. Morphological cytogenetic analysis demonstrated a colcemid-like effect of FAA on cytokinesis by causing accumulation of condensed C-metaphases of a sustained mitotic block. The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase. Based on these data, we propose that FAA may induce cell cycle arrest by stimulating the activity of acidic sphingomyelinase leading to the generation of reactive oxygen species.
Insights
Flavone acetic acid (FAA) causes cell cycle arrest in mammary carcinoma cells. This anti-cancer effect may involve reactive oxygen species generation.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Flavone acetic acid (FAA) is a synthetic flavonoid with demonstrated anti-tumour properties in animal models.
- FAA's clinical efficacy was limited, necessitating further investigation into its molecular mechanisms of action.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Flavone acetic acid's (FAA) anti-tumour activities.
- To examine the effect of FAA on the cell cycle progression of mammary carcinoma cells.
Main Methods:
- Cell cycle analysis of mammary carcinoma cells treated with FAA.
- Measurement of P34cdc2 (cdc2) cyclin-dependent kinase activity.
- Morphological and cytogenetic analysis to assess effects on mitosis and cytokinesis.
- Evaluation of the impact of antioxidants and specific inhibitors on FAA-induced cell cycle effects.
Main Results:
- FAA induced a G2/M cell cycle arrest in mammary carcinoma cells.
- Increased P34cdc2 (cdc2) activity was observed concurrently with cell cycle arrest.
- FAA exhibited a colcemid-like effect, causing mitotic block and C-metaphase accumulation.
- The cell cycle effects of FAA were mitigated by antioxidants (ADPC, ascorbate) and a superoxide scavenger (Tiron), but not by nitric oxide synthase inhibitors.
Conclusions:
- Flavone acetic acid (FAA) induces cell cycle arrest in mammary carcinoma cells.
- The mechanism may involve the stimulation of acidic sphingomyelinase, leading to reactive oxygen species (ROS) generation.
- FAA's anti-tumour effects are potentially mediated through ROS-dependent cell cycle disruption.