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

Authors
 Miran Jang  ;  Yeonghwan Kim  ;  Hyeran Won  ;  Sangbin Lim  ;  Jyothi K.R  ;  Amarjargal Dashdorj  ;  Yoo Hong Min  ;  Si-Young Kim  ;  Kevan M. Shokat  ;  Joohun Ha  ;  Sung Soo Kim 
Citation
 CANCER RESEARCH, Vol.72(16) : 4214-4224, 2012 
Journal Title
 CANCER RESEARCH 
ISSN
 0008-5472 
Issue Date
2012
MeSH
Alcohol Oxidoreductases/antagonists & inhibitors* ; Alcohol Oxidoreductases/biosynthesis ; Alcohol Oxidoreductases/genetics ; Alcohol Oxidoreductases/metabolism* ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; Apoptosis/drug effects ; Arsenicals/administration & dosage ; Arsenicals/pharmacology* ; Drug Synergism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacology* ; Female ; Gene Knockdown Techniques ; HL-60 Cells ; Humans ; K562 Cells ; Leukemia, Myeloid/drug therapy* ; Leukemia, Myeloid/enzymology* ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/pathology ; Mice ; Mice, Inbred BALB C ; NADPH Oxidases/metabolism ; Oxides/administration & dosage ; Oxides/pharmacology* ; Promoter Regions, Genetic ; Reactive Oxygen Species/metabolism ; Transcription Factor AP-1/metabolism ; U937 Cells ; Up-Regulation/drug effects ; Xenograft Model Antitumor Assays
Keywords
Alcohol Oxidoreductases/antagonists & inhibitors* ; Alcohol Oxidoreductases/biosynthesis ; Alcohol Oxidoreductases/genetics ; Alcohol Oxidoreductases/metabolism* ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; Apoptosis/drug effects ; Arsenicals/administration & dosage ; Arsenicals/pharmacology* ; Drug Synergism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacology* ; Female ; Gene Knockdown Techniques ; HL-60 Cells ; Humans ; K562 Cells ; Leukemia, Myeloid/drug therapy* ; Leukemia, Myeloid/enzymology* ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/pathology ; Mice ; Mice, Inbred BALB C ; NADPH Oxidases/metabolism ; Oxides/administration & dosage ; Oxides/pharmacology* ; Promoter Regions, Genetic ; Reactive Oxygen Species/metabolism ; Transcription Factor AP-1/metabolism ; U937 Cells ; Up-Regulation/drug effects ; Xenograft Model Antitumor Assays
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.
Full Text
http://cancerres.aacrjournals.org/content/72/16/4214
DOI
22719067
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/89870
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