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

Abstract

This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As 2 O 3 )-induced apoptosis. We showed that As 2 O 3 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 As 2 O 3 . Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As 2 O 3 -mediated Bax activation and apoptosis, and this inhibition could be partially averted by cellpermeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As 2 O 3 were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As 2 O 3 seemed to require stress-induced intracellular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-Lcysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As 2 O 3 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.

A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

“…[2][3][4] The activity of As 2 O 3 in APL is, in part, related to the disappearance of the promyelocytic leukemia (PML)/retinoic acid receptor (RAR)a fusion protein, the gene product of the chromosomal translocation t(15,17) characteristic of APL, and the induction of differentiation. 5,6 In addition, As 2 O 3 deregulates numerous proteins through binding to sulfhydryl groups, 7 inhibits mitochondrial respiratory function 8 and induces Bax oligomerization, 9 triggering apoptosis in non-APL cell lines. Considerable evidence suggests that As 2 O 3 induces the generation of reactive oxygen species (ROS).…”

Activation of Bak and Bax through c-Abl-Protein Kinase Cδ-p38 MAPK Signaling in Response to Ionizing Radiation in Human Non-small Cell Lung Cancer Cells

“…Multidomain pro-apoptotic members of the Bcl-2 family, Bax and Bak can facilitate mitochondrial dysfunction-mediated apoptosis, in response to various stimuli, such as cisplatin, etoposide, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), or arsenic trioxide, through homo-oligomerization dependent on their activity-related conformational changes (11,38,39). We found that ionizing radiationinduced apoptotic cell death involves induction of the apoptotic conformation and subsequent oligomerization of Bak and Bax.…”

The role of Akt on Arsenic trioxide suppression of 3T3-L1 preadipocyte differentiation

“…This could be due to the induction of differentiation at lower dose or induction of apoptosis or autophagic cell death at higher dose [7]. Others and we have reported that arsenic at clinically achievable dosage induced apoptosis by activating mitochondrial dependent apoptosis [8,9]. It is not surprising that arsenic trioxide could disrupt multiple signaling pathways for mitogenesis, differentiation, apoptosis and cell cycle control [10,11].…”