Catalase activity and arsenic sensitivity in acute leukemia

Arsenic trioxide (As(2)O(3)) is currently employed as a treatment for relapsed acute promyelocytic leukemia (APL), where it can induce remission in greater than 90% of patients, but is ineffective in patients with non-APL acute myeloid leukemia (AML). As(2)O(3) induces apoptosis in APL cells through mechanisms dependent and independent of the PML-RAR fusion protein. Through PML-RAR fusion-independent mechanisms, As(2)O(3) increases H(2)O(2) production via its effects on glutathione and glutathione peroxidase. Catalase is an alternative mechanism to convert H(2)O(2) to water. Therefore, we explored the relationship between catalase activity and As(2)O(3) sensitivity. In AML and APL cell lines, but not primary patient samples, basal catalase levels matched sensitivity to As(2)O(3). However, the chemical inhibition of catalase did not enhance As(2)O(3)-induced cell death. Failure of catalase inhibition to sensitise cells to As(2)O(3) was due to a failure of catalase inhibition to increased levels of reactive oxygen species. Therefore, other strategies should be explored to enhance the cytotoxicity of As(2)O(3) in AML.