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 delta(7)-prostaglandin A1 (PGA1) methyl ester. The MRP mRNA level in HL-60/R-CP cells increased remarkably after a 24-h incubation with 20 microM 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 delta(7)-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 delta(7)-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.
Akimaru
K
K
Department of Experimental Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Kuo
M T
MT
Furuta
K
K
Suzuki
M
M
Noyori
R
R
Ishikawa
T
T
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D016259:Genes, myc; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016133:Polymerase Chain Reaction; D011455:Prostaglandins A, Synthetic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002945:Cisplatin; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011455:Prostaglandins A, Synthetic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C048481:9-oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester