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2005
Journal Article
Titel
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 E2 (PGE2)-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, co-expression 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 PGE2 release (determined by flow cytometry, rhodamine123 efflux assay, RT-PCR, ELISA). After pre-incubation 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 MTT 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 PGE2 pre-incubation. In conclusion, the cyclooxygenase system, especially the cyclooxygenase-2 isoform, might be involved in regulating doxorubicin-induced MDR1 overexpression in AML cells, with PGE2 appearing to be a mediating factor. Cyclooxygenase inhibitors thus bear promise to overcome MDR in AML and improve therapy.
Author(s)
Puhlmann, U.
University of Münster / Department of Pediatric Hematology and Concology <Münster, Germany>>
Vorwerk, H.
University of Münster / Department of Pediatric Hematology and Concology <Münster, Germany>
Schaefer, D.
University of Heidelberg / Competence Center for Environmental Health, Clinic for Ear, Nose, and Throat, Faculty of Clinical Medicine <Mannheim, Germany>
Langebrake, C.
University of Münster / Department of Pediatric Hematology and Concology <Münster, Germany>
Creutzig, U.
University of Münster / Department of Pediatric Hematology and Concology <Münster, Germany>