Abstract
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.
Highlights
Carbonyl reductase 1 (CBR1) is a ubiquitous NADPH-dependent enzyme belonging to the short-chain dehydrogenase/ reductase family [1]
Our findings indicate that carbonyl reductase 1 (CBR1) contributes to the low efficacy of As2O3 and, is a rational target for the development of combination chemotherapy with As2O3 in diverse leukemias including acute promyelocytic leukemia (APL)
CBR1 is upregulated at the transcriptional level by As2O3 To investigate whether CBR1 is induced by As2O3, we first conducted Western blot analysis on total cell lysates from the leukemia cell lines following treatment with As2O3
Summary
Carbonyl reductase 1 (CBR1) is a ubiquitous NADPH-dependent enzyme belonging to the short-chain dehydrogenase/ reductase family [1]. This enzyme catalyzes a significant number of biologically and pharmacologically active substrates, including a variety of endogenous and xenobiotic carbonyl compounds [2]. The best substrates of CBR1 are quinones, including ubiquinone-1 and tocopherolquinone (vitamin E). Ubiquinone (coenzyme Q) is a constitutive factor in the respiratory chain, and tocopherolquinone protects the lipids of biological membranes against lipid peroxidation, indicating that CBR1 plays an important role as an oxidation–reduction catalyst in cellular processes [3]. Overexpression of Authors' Affiliations: 1Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine; 2Department of Medical Oncology & Hematology, Kyung Hee Medical Center, Kyung Hee University; 3Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, Korea; and 4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California
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