Data from Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide

Arsenic trioxide (As₂O₃) is used, in current practice, as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). However, the side effects and relatively low efficacy of As₂O₃ in treating other leukemias have limited its wider use in therapeutic applications. In the present study, we found that the expression of carbonyl reductase 1 (CBR1) affects the resistance to As₂O₃ in leukemias, including APL; As₂O₃ upregulated CBR1 expression at the transcriptional level by stimulating the activity of the transcription factor activator protein-1. Moreover, CBR1 overexpression was sufficient to protect cells against As₂O₃ through modulation of the generation of reactive oxygen species, whereas the attenuation of CBR1 was sufficient to sensitize cells to As₂O₃. A combination treatment with the specific CBR1 inhibitor hydroxy-PP-Me remarkably increased As₂O₃-induced apoptotic cell death compared with As₂O₃ alone, both in vitro and in vivo. These results were confirmed in primary cultured human acute and chronic myeloid leukemia cells, with no significant cell death observed in normal leukocytes. Taken together, our findings indicate that CBR1 contributes to the low efficacy of As₂O₃ and, therefore, is a rational target for the development of combination chemotherapy with As₂O₃ in diverse leukemias including APL. Cancer Res; 72(16); 4214–24. ©2012 AACR.