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The synthetic flavonoid flavone acetic acid (FAA) has anti-tumor activity against a variety of transplanted tumors in mice through mechanisms which likely involve effects on tumor vasculature and the host immune system. The aims of the present in vitro study were to compare the sensitivity of tumor and endothelial cells to FAA treatment and to assess if nitric oxide and superoxide are involved in the FAA-mediated suppression of cell proliferation. FAA at 1 mM concentration was approximately two times more effective in suppressing proliferation of endothelial than tumor cells. The anti-proliferative effect of 1 mM FAA on endothelial cells was partially blocked by inhibitors to various superoxide-producing enzymes (xanthine oxidase, cyclooxygenase, poly-ADP-ribose polymerase, ribonucleotide reductase) and completely inhibited by the direct scavengers of superoxide lucigenin and Tiron. In contrast, inhibitors of nitric oxide were unable to prevent the effects of FAA on proliferation. FAA induced apoptosis of endothelial cells, which was not affected by inhibitors of nitric oxide or superoxide. Our data imply that FAA inhibits proliferation of endothelial cells by a superoxide-dependent mechanism and induces apoptosis by a nitric oxide and superoxide-independent mechanism.