Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells.
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.
Panaro
N J
NJ
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Popescu
N C
NC
Harris
S R
SR
Thorgeirsson
U P
UP
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D003523:Cycloserine / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005434:Flow Cytometry / Q000379:methods; D016195:G2 Phase / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental; D008677:Metaphase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D008940:Mitotic Index / Q000187:drug effects; D012334:RNA, Neoplasm / Q000032:analysis; D051381:Rats; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005419:Flavonoids; D012334:RNA, Neoplasm; C049328:flavone acetic acid; D003523:Cycloserine; D016203:CDC2 Protein Kinase