Catalase activity and arsenic sensitivity in acute leukemia

Abstract

Arsenic trioxide (As₂O₃) 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). As₂O₃ induces apoptosis in APL cells through mechanisms dependent and independent of the PML-RARα fusion protein. Through PML-RARα fusion-independent mechanisms, As₂O₃ increases H₂O₂ production via its effects on glutathione and glutathione peroxidase. Catalase is an alternative mechanism to convert H₂O₂ to water. Therefore, we explored the relationship between catalase activity and As₂O₃ sensitivity. In AML and APL cell lines, but not primary patient samples, basal catalase levels matched sensitivity to As₂O₃. However, the chemical inhibition of catalase did not enhance As₂O₃-induced cell death. Failure of catalase inhibition to sensitise cells to As₂O₃ 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 As₂O₃ in AML.

Keywords:

• Chemotherapeutic approaches
• neoplasia
• myeloid leukemias
• dysplasia
• pharmacotherapeutics