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 that cytotoxicity is the sole mechanism of action. We have used a myelomonocytic
leukemia cell line (U937) to characterize the concentration-dependent effects of
arsenite on cell growth, viability, apoptosis, and differentiation.
Arsenite has multiple effects on U937 cells. Low concentrations of
arsenite (i.e., < or = 1 microM) potentiate vitamin-D(3)-induced differentiation. Two markers of monocyte differentiation, Mac-1 expression and
nitroblue tetrazolium reduction, are increased in
arsenite-exposed, D(3)-costimulated cells. Concentrations of
arsenite >10 microM rapidly induce the death of cells irrespective of cell cycle phase. Intermediate concentrations of
arsenite (i.e., 5 to 10 microM) are
cytostatic initially. Cell cycle analysis using elutriated, synchronous cell populations revealed that intermediate concentrations of
arsenite delay both G(1) and G(2) transit. G(2) cells appear 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
caspase-3 dependent.
Arsenite-mediated cytotoxicity was reduced in the presence of the broad
caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone; however,
caspase inhibition did not reverse
arsenite-induced cytostasis. Thus,
arsenite has multiple effects on U937 cells that are dependent on concentration and cell cycle phase. Specifically, cell cycle transit and differentiation are more sensitive to
arsenite than is the induction of apoptosis.