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.
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Abbreviations
- GS-conjugate:
-
glutathione S-conjugate
- GSH:
-
glutathione reduced form
- GSSG:
-
glutathione disulfide
- GS-X pump:
-
ATP-dependent glutathione S-conjugate export pump
- MRP :
-
multidrug resistance-associated protein
- PG:
-
prostaglandin
- RT-PCR:
-
reverse transcriptase-polymerase chain reaction
- YCF1 :
-
yeast cadmium factor 1
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Akimaru, K., Kuo, M.T., Furuta, K. et al. Induction ofMRP/GS-X pump and cellular resistance to anticancer prostaglandins. Cytotechnology 19, 221–227 (1996). https://doi.org/10.1007/BF00744216
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DOI: https://doi.org/10.1007/BF00744216