Abstract
To enhance the therapeutic effects and decrease the adverse effects of arsenic on the treatment of acute promyelocytic leukemia, we investigated the co-effects of selenite (Se(4+)) and arsenite (As(3+)) on the apoptosis and differentiation of NB4 cells and primary APL cells. A 1.0-μM concentration of Se(4+) prevented the cells from undergoing As(3+)-induced apoptosis by inhibiting As(3+) uptake, eliminating As(3+)-generated reactive oxygen species, and repressing the mitochondria-mediated intrinsic apoptosis pathway. However, 4.0 μM Se(4+) exerted synergistic effects with As(3+) on cell apoptosis by promoting As(3+) uptake, downregulating nuclear factor-кB, and activating caspase-3. In addition to apoptosis, 1.0 and 3.2 μM Se(4+) showed contrasting effects on As(3+)-induced differentiation in NB4 cells and primary APL cells. The 3.2 μM Se(4+) enhanced As(3+)-induced differentiation by promoting the degradation of promyelocytic leukemia protein-retinoic acid receptor-α (PML-RARα) oncoprotein, but 1.0 μM Se(4+) did not have this effect. Based on mechanistic studies, Se(4+), which is similar to As(3+), might bind directly to Zn(2+)-binding sites of the PML RING domain, thus controlling the fate of PML-RARα oncoprotein.