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 M 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.
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