Document Detail


Sensitivity of K562 and HL-60 cells to edelfosine, an ether lipid drug, correlates with production of reactive oxygen species.
MedLine Citation:
PMID:  9661895     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; ET-18-OCH3), a membrane-targeting anticancer ether lipid drug has been shown previously in vitro to be capable of initiating oxidative processes in cells. Here we study two human leukemia cell lines (HL-60 and K562) that have different sensitivities to edelfosine; HL-60 cells are more sensitive than K562 cells. To determine whether edelfosine alters the sensitivity of these lines to an oxidative stress, cells were subjected to the oxidative stress of iron(II) plus ascorbate and then monitored for free radical formation, membrane integrity, and cytotoxicity. The HL-60 cell was sensitive to the ether lipid drug in clonogenic and dye exclusion assays; a lipid-derived free radical was generated by this sensitive cell in the presence of small amounts of Fe2+ and ascorbate as detected by electron paramagnetic resonance and the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone. There was also simultaneous generation of an ascorbate-free radical, which has been shown to estimate cellular oxidative flux. In contrast, the K562 cell was resistant to edelfosine cytotoxicity in all assays and did not generate either lipid-derived or ascorbate-free radicals. Subcellular homogenates of the HL-60 cell generated both radicals when exposed to the drug, but homogenates of K562 did not generate either, suggesting that differential drug uptake or intracellular drug localization is not the cause of the difference in oxidation. Trypan blue uptake by the HL-60, but not the K562 cells, measured under the same conditions as the oxidation experiments, demonstrated a loss of membrane impermeability with similar time and concentration dependence, suggesting a causal relationship of membrane damage and radical generation. Complementary studies of HL-60 cell membrane integrity with propidium iodide impermeability and light scatter using the flow cytometer showed a concentration dependence that was similar to radical generation. Biochemical studies of the fatty acids of the HL-60 cell revealed more highly polyunsaturated lipids in the cells. Cellular antioxidant enzymes and vitamin E contents of the two cell lines were similar. We conclude that there is a time- and concentration-dependent generation of important oxidations by the sensitive HL-60 cells exposed to the membrane-targeted ether lipid, but the resistant K562 cells are oxidatively silent. This may be due in part to the differences in fatty acid polyunsaturation of the cellular membranes. The difference in oxidative susceptibility could be the basis for drug resistance to this membrane-specific anticancer agent.
Authors:
B A Wagner; G R Buettner; L W Oberley; C P Burns
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  58     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1998 Jul 
Date Detail:
Created Date:  1998-07-23     Completed Date:  1998-07-23     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2809-16     Citation Subset:  IM    
Affiliation:
Department of Medicine, The University of Iowa College of Medicine, The University of Iowa Cancer Center, Iowa City 52242, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Ascorbic Acid / pharmacology
Cell Membrane / drug effects
Fatty Acids / chemistry
Flow Cytometry
Free Radicals / metabolism
HL-60 Cells / drug effects,  metabolism
Humans
Indicators and Reagents / metabolism
Iron / pharmacology
Lipid Peroxidation
Nitrogen Oxides / pharmacology
Phospholipid Ethers / pharmacology*
Propidium / metabolism
Pyridines
Reactive Oxygen Species / metabolism*
Trypan Blue / metabolism
Tumor Cells, Cultured / drug effects*,  metabolism
Vitamin E / analysis
Grant Support
ID/Acronym/Agency:
HL49264/HL/NHLBI NIH HHS; P01 CA66081/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Fatty Acids; 0/Free Radicals; 0/Indicators and Reagents; 0/Nitrogen Oxides; 0/Phospholipid Ethers; 0/Pyridines; 0/Reactive Oxygen Species; 0/alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone; 1406-18-4/Vitamin E; 36015-30-2/Propidium; 50-81-7/Ascorbic Acid; 65492-82-2/edelfosine; 72-57-1/Trypan Blue; 7439-89-6/Iron

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


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