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.
Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
Miran
M
Jang
Yeonghwan
Y
Kim
Hyeran
H
Won
Sangbin
S
Lim
Jyothi
J
K R
Amarjargal
A
Dashdorj
Yoo Hong
YH
Min
Si-Young
SY
Kim
Kevan M
KM
Shokat
Joohun
J
Ha
Sung Soo
SS
Kim
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019255:NADPH Oxidases / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D001152:Arsenicals; D004791:Enzyme Inhibitors; D010087:Oxides; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; D019255:NADPH Oxidases; D000077237:Arsenic Trioxide