Impact of the cyclooxygenase system on doxorubicin-induced functional multidrug resistance 1 overexpression and doxorubicin sensitivity in acute myeloid leukemic HL-60 cells.

Abstract

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.

• Authors: Ulrike Puhlmann, Christina Ziemann, Gudrun Ruedell, Hagen Vorwerk, Dirk Schaefer, Claudia Langebrake, Peter Schuermann, Ursula Creutzig, Dirk Reinhardt
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 312 Issue 1 Pg. 346-54 (Jan 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15501994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Membrane Proteins
• Thiazines
• Thiazoles
• Rhodamine 123
• Doxorubicin
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone
• Meloxicam

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Apoptosis
• 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
• Humans
• Leukemia, Myeloid, Acute
• Meloxicam
• Membrane Proteins
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Rhodamine 123 (pharmacology)
• Thiazines (pharmacology)
• Thiazoles (pharmacology)