Schedule and concentration-dependent induction of apoptosis in leukemia cells by nitric oxide.

Nitric oxide (NO) has potent antiproliferative properties. In previous work we have shown that NO inhibits growth, induces differentiation and modulates gene expression in acute nonlymphocytic leukemia (ANLL) cells. The goal of this work was to determine whether the rate of NO delivery affected its growth inhibition of ANLL cells. We also wanted to determine whether the NO inhibition of ANLL cell growth is associated with the induction of apoptosis. We treated HL-60 and U937 cells with three compounds that generate the same amount of NO but at different rates. MAMA-NO, PAPA-NO and DETA-NO have half-lives of NO delivery of 2 and 30 min, and 20 h, respectively. The compound with the longest t(1/2) of NO delivery (DETA-NO) was the most potent inhibitor of leukemia cell and colony growth. Furthermore, the NO-induced growth inhibition was associated with apoptosis in a rate and concentration-dependent fashion.