Arsenic trioxide induces dose- and time-dependent apoptosis of endotheliumand may exert an antileukemic effect via inhibition of angiogenesis

Arsenic trioxide (As2O3) has recently been used successfully in the treatme nt of acute promyelocytic leukemia and has been shown to induce partial dif ferentiation and apoptosis of leukemic cells in vitro. However, the mechani sm by which As2O3 exerts its antileukemic effect remains uncertain. Emergin g data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that a ctivated endothelial cells release cytokines that may stimulate leukemic ce ll growth. Leukemic cells, in turn, can release endothelial growth factors, such as Vascular endothelial growth factor (VEGF). On the basis of these o bservations, we hypothesized that As2O3 may interrupt a reciprocal loop bet ween leukemic cells and the endothelium by direct action on both cell types . We have shown that treatment of proliferating layers of human umbilical v ein endothelial cells (HUVECs) with a variety of concentrations of As2O3 re sults in a reproducible dose and time-dependent sequence of events marked b y change to an activated morphology, upregulation of endothelial cell adhes ion markers, and apoptosis. Also, treatment with As2O3 caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVE Cs with As2O3 prevented capillary tubule and branch formation in an in vitr o endothelial cell-differentiation assay. In conclusion, we believe that As 2O3 interrupts a reciprocal stimulatory loop between leukemic cells and end othelial cells by causing apoptosis of both cell types and by inhibiting le ukemic cell VEGF production. (Blood. 2000;96:1525-1530) (C) 2000 by The Ame rican Society of Hematology.