Document Detail


Inhibition of AMP-activated protein kinase pathway sensitizes human leukemia K562 cells to nontoxic concentration of doxorubicin.
MedLine Citation:
PMID:  20339906     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Doxorubicin (Dox) is a commonly used anthracycline in many antitumor regimens. The dose related Dox-induced cardiotoxicity often poses challenge in clinical practice, lowering its dose and administering it in combination with other compound is an option. In this study, we found that a nontoxic concentration of Dox at 34.5 nM (20 ng/ml) combined with Compound C, an inhibitor used in AMP-activated protein kinase (AMPK) pathway, could kill human leukemia K562 cells. Additionally, this study confirmed that the combined effect was related to the inhibition of some key proteins such as AMPK and acetyl CoA carboxylase. Moreover, down-regulation of these key proteins in AMPK pathway using siRNA technology also sensitized K562 cells to nontoxic concentration of Dox. The study also showed that Dox at a concentration of 345.0 nM (200 ng/ml) or 862.0 nM (500 ng/ml) that is lower than a typical value of 1-2 microM Dox in patients could kill human leukemia K562 cells. Taken together, our results suggest that inhibition of AMPK pathway by Compound C or siRNA sensitizes K562 cells to nontoxic concentration of Dox which is much lower than typical concentration in plasma of clinical patients.
Authors:
Qun Zhu; Bo Shen; Boshao Zhang; Wei Zhang; Steve H Chin; Junfei Jin; Duan-fang Liao
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-26
Journal Detail:
Title:  Molecular and cellular biochemistry     Volume:  340     ISSN:  1573-4919     ISO Abbreviation:  Mol. Cell. Biochem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-15     Completed Date:  2010-09-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0364456     Medline TA:  Mol Cell Biochem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  275-81     Citation Subset:  IM    
Affiliation:
Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, People's Republic of China.
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MeSH Terms
Descriptor/Qualifier:
AMP-Activated Protein Kinases / antagonists & inhibitors*,  genetics,  metabolism
Acetyl-CoA Carboxylase / antagonists & inhibitors,  genetics,  metabolism
Antibiotics, Antineoplastic / pharmacology
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Doxorubicin / pharmacology
Humans
K562 Cells
Leukemia, Erythroblastic, Acute / enzymology*,  genetics,  pathology
Protein Kinase Inhibitors / pharmacology
Pyrazoles / pharmacology
Pyrimidines / pharmacology
RNA Interference
Chemical
Reg. No./Substance:
0/(6-(4-(2-piperidin-1-ylethoxy)phenyl))-3-pyridin-4-ylpyrazolo(1,5-a)pyrimidine; 0/Antibiotics, Antineoplastic; 0/Protein Kinase Inhibitors; 0/Pyrazoles; 0/Pyrimidines; 23214-92-8/Doxorubicin; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 6.4.1.2/Acetyl-CoA Carboxylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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