Document Detail

Impact of the cyclooxygenase system on doxorubicin-induced functional multidrug resistance 1 overexpression and doxorubicin sensitivity in acute myeloid leukemic HL-60 cells.
MedLine Citation:
PMID:  15501994     Owner:  NLM     Status:  MEDLINE    
Multidrug resistance (MDR), a challenge in treating childhood acute myeloid leukemia (AML), is frequently associated with decreased drug accumulation caused by multidrug transporter MDR1. Doxorubicin, an important anti-AML drug, is a known MDR1 substrate and inducer. Its cytostatic efficacy is thus limited by MDR1 overexpression. A recent study demonstrated cyclooxygenase-2-dependent, prostaglandin E(2) (PGE(2))-mediated regulation of mdr1b expression in primary rat hepatocyte cultures. Cyclooxygenase-2 expression is increased in several malignancies and considered a negative prognostic factor. Our study focused on cyclooxygenase system's impact on drug-induced MDR1 overexpression in AML cells. As a prerequisite, coexpression of MDR1 and cyclooxygenase-2 mRNA in HL-60 cells and primary AML blasts was demonstrated by Northern blot. Interestingly, incubation of AML cells with doxorubicin not only induced functionally active MDR1 overexpression but also mediated increased cyclooxygenase-2 mRNA and protein expressions with subsequent PGE(2) release (determined by flow cytometry, rhodamine123 efflux assay, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay). After preincubation and subsequent parallel treatment with the cyclooxygenase-2-preferential inhibitor meloxicam, doxorubicin-induced MDR1 overexpression and function were reduced (maximally at 0.1-0.5 microM meloxicam), whereas cytostatic efficacy of doxorubicin in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays was significantly increased by up to 78 (HL-60) and 30% (AML blasts) after 72 h of doxorubicin treatment. In HL-60 cells, meloxicam-dependent effect on doxorubicin cytotoxicity was neutralized by PGE(2) preincubation. In conclusion, the cyclooxygenase system, especially the cyclooxygenase-2 isoform, might be involved in regulating doxorubicin-induced MDR1 overexpression in AML cells, with PGE(2) seeming to be a mediating factor. Cyclooxygenase inhibitors thus bear promise to overcome MDR in AML and improve therapy.
Ulrike Puhlmann; Christina Ziemann; Gudrun Ruedell; Hagen Vorwerk; Dirk Schaefer; Claudia Langebrake; Peter Schuermann; Ursula Creutzig; Dirk Reinhardt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-10-22
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  312     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-16     Completed Date:  2005-04-13     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  346-54     Citation Subset:  IM    
AML-BFM Study, Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Str. 33, 48129 Muenster, Germany.
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MeSH Terms
Biological Transport
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / pharmacology
Dinoprostone / metabolism
Doxorubicin / adverse effects*
Drug Interactions
Drug Resistance, Multiple
Drug Resistance, Neoplasm / physiology*
Drug Screening Assays, Antitumor
Gene Expression / drug effects
HL-60 Cells
Leukemia, Myeloid, Acute
Membrane Proteins
P-Glycoprotein / metabolism*
Prostaglandin-Endoperoxide Synthases / metabolism*
Rhodamine 123 / pharmacology
Thiazines / pharmacology
Thiazoles / pharmacology
Reg. No./Substance:
0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Membrane Proteins; 0/P-Glycoprotein; 0/Thiazines; 0/Thiazoles; 23214-92-8/Doxorubicin; 363-24-6/Dinoprostone; 62669-70-9/Rhodamine 123; 71125-38-7/meloxicam; EC 2; EC protein, human; EC Synthases

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