Sensitivity of myelomonocytic leukemia cells to arsenite-induced cell cycle disruption, apoptosis, and enhanced differentiation is dependent on the inter-relationship between arsenic concentration, duration of treatment, andcell cycle phase

Arsenite treatment has been found to induce clinical remission in patients with acute promyelocytic leukemia. Although the potential therapeutic value of arsenite may lie in triggering apoptosis, it has not been established t hat cytotoxicity is the sole mechanism of action. We have used a myelomonoc ytic leukemia cell line (U937) to characterize the concentration-dependent effects of arsenite on cell growth, viability, apoptosis, and differentiati on. Arsenite has multiple effects on U937 cells. Low concentrations of arse nite (i.e., less than or equal to1 mM) potentiate vitamin-D-3-induced diffe rentiation. Two markers of monocyte differentiation, Mac-1 expression and n itroblue tetrazolium reduction, are increased in arsenite-exposed, D-3-cost imulated cells. Concentrations of arsenite >10 muM rapidly induce the death of cells irrespective of cell cycle phase. Intermediate concentrations of arsenite (i.e., 5 to 10 muM) are cytostatic initially. Cell cycle analysis using elutriated, synchronous cell populations revealed that intermediate c oncentrations of arsenite delay both G(1) and G(2) transit. G(2) cells appe ar to be most sensitive to arsenite, in that transit through G(2)/M is more delayed than transit through G(1), and apoptosis is induced in these cells as they emerge from an aberrant G(2/M.) Arsenite-induced apoptosis was cas pase-3 dependent. Arsenite-mediated cytotoxicity was reduced in the presenc e of the broad caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone; howev er, caspase inhibition did not reverse arsenite-induced cytostasis. Thus, a rsenite has multiple effects on U937 cells that are dependent on concentrat ion and cell cycle phase. Specifically, cell cycle transit and differentiat ion are more sensitive to arsenite than is the induction of apoptosis.