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, and cell 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 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, apopto-sis, and differentiation. Arsenite has multiple effects on U937 cells. Low concentrations of arsenite (i.e., #1 mM) potentiate vitamin-D3-induced differentiation. Two markers of monocyte differentiation, Mac-1 expression and nitroblue tetrazolium re-duction, are increased in arsenite-exposed, D3-costimulated cells. Concentrations of arsenite.10 mM rapidly induce the death of cells irrespective of cell cycle phase. Intermediat