Arsenic trioxide (As₂O₃) induces apoptosis through activation of Bax in hematopoietic cells

This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As₂O₃)-induced apoptosis. We showed that As₂O₃ treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As₂O₃. Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As₂O₃-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As₂O₃ were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As₂O₃ seemed to require stress-induced intracelular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As₂O₃ might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.