Carbonyl reductase 1 offers a novel therapeutic target to enhance leukemia treatment by arsenic trioxide

摘要

Arsenic trioxide (As 2O 3) is used, in current practice, as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). However, the side effects and relatively low efficacy of As 2O 3 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 As 2O 3 in leukemias, including APL; As 2O 3upregulated 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 As 2O 3 through modulation of the generation of reactive oxygen species, whereas the attenuation of CBR1 was sufficient to sensitize cells to As 2O 3. A combination treatment with the specific CBR1 inhibitor hydroxy-PP-Me remarkably increased As 2O 3-induced apoptotic cell death compared with As 2O 3 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 As 2O 3 and, therefore, is a rational target for the development of combination chemotherapy with As 2O 3 in diverse leukemias including APL.