Dose-dependent effects of selenite (Se4+) on arsenite (As3+)-induced apoptosis and differentiation in acute promyelocytic leukemia cells

摘要

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 (Se⁴⁺) and arsenite (As³⁺) on the apoptosis and differentiation of NB4 cells and primary APL cells. A 1.0-μM concentration of Se⁴⁺ prevented the cells from undergoing As³⁺-induced apoptosis by inhibiting As³⁺ uptake, eliminating As³⁺-generated reactive oxygen species, and repressing the mitochondria-mediated intrinsic apoptosis pathway. However, 4.0 μM Se⁴⁺ exerted synergistic effects with As³⁺ on cell apoptosis by promoting As³⁺ uptake, downregulating nuclear factor-кB, and activating caspase-3. In addition to apoptosis, 1.0 and 3.2 μM Se⁴⁺ showed contrasting effects on As³⁺-induced differentiation in NB4 cells and primary APL cells. The 3.2 μM Se⁴⁺ enhanced As³⁺-induced differentiation by promoting the degradation of promyelocytic leukemia protein–retinoic acid receptor-α (PML–RARα) oncoprotein, but 1.0 μM Se⁴⁺ did not have this effect. Based on mechanistic studies, Se⁴⁺, which is similar to As³⁺, might bind directly to Zn²⁺-binding sites of the PML RING domain, thus controlling the fate of PML–RARα oncoprotein.