Impact of the cyclooxygenase system on doxorubicin-induced functional multidrug resistance 1 overexpression and doxorubicin sensitivity in acute myeloid leukemic HL-60 cells
2005 | conference paper. A publication with affiliation to the University of Göttingen.
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Impact of the cyclooxygenase system on doxorubicin-induced functional multidrug resistance 1 overexpression and doxorubicin sensitivity in acute myeloid leukemic HL-60 cells
Puhlmann, U.; Ziemann, C.; Ruedell, G.; Vorwerk, H.; Schaefer, D.; Langebrake, C. & Schuermann, P. et al. (2005)
Journal of Pharmacology and Experimental Therapeutics, 312(1) pp. 346-354. 44th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology, Mainz, GERMANY.
Bethesda: Amer Soc Pharmacology Experimental Therapeutics. DOI: https://doi.org/10.1124/jpet.104.071571
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- Authors
- Puhlmann, U.; Ziemann, C.; Ruedell, G.; Vorwerk, Hilke; Schaefer, D.; Langebrake, C.; Schuermann, P.; Creutzig, Ursula; Reinhardt, D.
- 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 muM 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.
- Issue Date
- 2005
- Status
- published
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Journal
- Journal of Pharmacology and Experimental Therapeutics
- Conference
- 44th Spring Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology
- Conference Place
- Mainz, GERMANY
- ISSN
- 0022-3565