Oxidative stress contributes to the anti-proliferative effects of flavone acetic acid on endothelial cells

The synthetic flavonoid flavone acetic acid (FAA) has anti-tumor activity a gainst a variety of transplanted tumors in mice through mechanisms which li kely involve effects on tumor vasculature and the host immune system. The a ims 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 su peroxide are involved in the FAA-mediated suppression of cell proliferation . FAA at 1 mM concentration was approximately two times move effective in s uppressing proliferation of endothelial than tumor cells. The antiprolifera tive effect of 1 mM FAA on endothelial cells was partially blocked by inhib itors to various superoxide-producing enzymes (xanthine oxidase, cyclooxyge nase, poly-ADP-ribose polymerase, ribonucleotide reductase) and completely inhibited by the direct scavengers of superoxide lucigenin and Tiron. In co ntrast, inhibitors of nitric oxide were unable to prevent the effects of PA A on proliferation. FAA induced apoptosis of endothelial cells, which was n ot affected by inhibitors of nitric oxide or superoxide. Our data imply tha t FAA inhibits proliferation of endothelial cells by a superoxide-dependent mechanism and induces apoptosis by a nitric oxide and superoxide-independe nt mechanism.