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

We provide evidence that the expression of the human MRP/GS-X pump encoded by the MRP (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. The MRP mRNA level in HL60/R-CP cells increased remarkably after a 24- h incubation with 20 μM cisplatin; interestingly, however, no amplification of the MRP gene was detected. In cisplatin-sensitive HL-60 cells, which express the MRP/GS-X pump at low levels, c-myc expression was substantially suppressed by Δ⁷-PGA₁ methyl ester and the cell cycle was arrested in G1 phase. By contrast, in HL-60/R-CP cells overexpressing the MRP/GS-X pump, c- myc expression and cell proliferation were much less affected by Δ⁷-PGA₁ methyl ester. This suggests that induction of the MRP/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 the MRP/GS-X pump.