Tetraarsenic Hexoxide Induces Beclin-1-Induced Autophagic Cell Death as well as Caspase-Dependent Apoptosis in U937 Human Leukemic Cells

Tetraarsenic hexaoxide (As(4)O(6)) has been used in Korean folk remedy for the treatment of cancer since the late 1980s, and arsenic trioxide (As(2)O(3)) is currently used as a chemotherapeutic agent. However, evidence suggests that As(4)O(6)-induced cell death pathway was different from that of As(2)O(3). Besides, the anticancer effects and mechanisms of As(4)O(6) are not fully understood. Therefore, we investigated the anticancer activities of As(4)O(6) on apoptosis and autophagy in U937 human leukemic cells. The growth of U937 cells was inhibited by As(4)O(6) treatment in a dose- and a time-dependent manner, and IC(50) for As(4)O(6) was less than 2 μM. As(4)O(6) induced caspase-dependent apoptosis and Beclin-1-induced autophagy, both of which were significantly attenuated by Bcl-2 augmentation and N-acetylcysteine (NAC) treatment. This study suggests that As(4)O(6) should induce Beclin-1-induced autophagic cell death as well as caspase-dependent apoptosis and that it might be a promising agent for the treatment of leukemia.