Very little is known concerning the toxicity of
antimony, despite its commercial use as a
flame retardant and medical use as a treatment for
parasitic infections. Our previous studies show that
antimony trioxide (Sb(2)O(3)) induces growth inhibition in patient-derived
acute promyelocytic leukemia (APL) cell lines, a disease in which a related
metal,
arsenic trioxide (
As(2)O(3)), is used clinically. However, signaling pathways initiated by Sb(2)O(3) treatment remain undefined. Here, we show that Sb(2)O(3) treatment of APL cells is associated with increased apoptosis as well as
differentiation markers. Sb(2)O(3)-induced
reactive oxygen species (ROS) correlated with increased apoptosis. In addition, when we decreased the buffering capacity of the cell by depleting
glutathione, ROS production and apoptosis was enhanced.
Arsenic-resistant APL cells with increased
glutathione levels exhibited increased cross-resistance to Sb(2)O(3). Based on studies implicating c-jun
kinase (JNK) in the mediation of the response to
As(2)O(3), we investigated the role for JNK in Sb(2)O(3)-induced apoptosis. Sb(2)O(3) activates JNK and its downstream target,
AP-1. In fibroblasts with a genetic deletion in SEK1, an upstream regulator of JNK, Sb(2)O(3)-induced growth inhibition as well as JNK activation was decreased. These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure.