Induction ofMRP/GS-X pump and cellular resistance to anticancer prostaglandins

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Abstract
We provide evidence that the expression of the humanMRP/GS-X pump encoded by theMRP (multidrug resistance associated protein) gene is induced by cisplatin in human leukemia HL-60/R-CP (cisplatin-resistant) cells and modulates cell growth inhibition by Δ7-prostaglandin A1 (PGA1) methyl ester. TheMRP mRNA level in HL-60/R-CP cells increased remarkably after a 24-h incubation with 20 μM cisplatin; interestingly, however, no amplification of theMRP gene was detected. In cisplatin-sensitive HL-60 cells, which express theMRP/GS-X pump at low levels, c-myc expression was substantially supressed by Δ7-PGA1 methyl ester and the cell cycle was arrested in G1 phase. By contrast, in HL-60/R-CP cells overexpressing theMRP/GS-X pump, c-myc expression and cell proliferation were much less affected by Δ7-PGA1 methyl ester. This suggests that induction of theMRP/GS-X pump may confer on cancer cells resistance to anticancer prostaglandins and that the resistance mechanism may involve the increased efflux of PG-glutathione conjugates, as active intermediates, from the cells via theMRP/GS-X pump.